U.S. ENVIRONMENTAL PROTECTION AGENCY 

OFFICE OF INSPECTOR GENERAL 

Catalyst for Improving the Environment 

Science Review 

Office of Inspector General 

Scientific Analysis of Perchlorate 

Report No. 10-P-0101 

April 19, 2010 
Author and Reviewers 

Author 

Michael Wilson 

Toxicologist 

U.S. Environmental Protection Agency 

Office of Inspector General (OIG) 

Office of Program Evaluation (2460T) 

1200 Pennsylvania Ave, NW 

Washington, DC 20460 

Review 

Through solicitation number RFQ261223 (dated February 8, 2008), the OIG contracted with ICF 

Incorporated, LLC (ICF) under contract number GS-10F-0124J, to conduct a 6-week technical 

review of a working draft of the OIG Scientific Analysis of Perchlorate. The purpose of the 

technical review was to provide a scientific critique of the essential features of the OIG’s 

application of a cumulative risk assessment to this public health issue. 
 

 

U.S. Environmental Protection Agency 10-P-0101 

April 19, 2010 Office of Inspector General 

At a Glance 

Catalyst for Improving the Environment 

Why We Did This Review 

Stakeholders often dispute

the scientific support for a 

particular U.S. Environmental 

Protection Agency (EPA) 

decision or program action. 

We believe there is a particular

need for impartial reviews of 

EPA’s regulatory toxicology. 

Therefore, as a prototype for 

this work, we conducted an 

independent, scientific review 

of the risk assessment process 

and procedures used by EPA to 

develop and derive the 

perchlorate reference dose 

(RfD). 

Background 

On February 18, 2005, EPA 

issued a perchlorate RfD that 

corresponds to a drinking water 

equivalent level of 24.5 parts 

per billion. A regulatory

determination is pending on

whether to issue a National 

Primary Drinking Water 

Regulation. 

For further information, contact 

our Office of Congressional, 

Public Affairs and Management 

at (202) 566-2391. 

To view the full report, 

click on the following links: 

www.epa.gov/oig/reports/2010/ 

20100419-10-P-0101.pdf 

www.epa.gov/oig/reports/2010/ 

20100419-10-P-0101 appD.pdf 

www.epa.gov/oig/reports/2010/ 

20100419-10-P-0101 appE.pdf 

Office of Inspector General Scientific Analysis 

of Perchlorate

 What We Found 

EPA should conduct a cumulative risk assessment to reduce the uncertainty in 

characterizing the public health risk posed by perchlorate. A cumulative risk 

assessment is the current state-of-the-art technique for evaluating the public 

health risk from multiple stressors. Over the last two decades, EPA has received 

numerous recommendations to improve environmental risk assessments. In 

1997, EPA Administrator Carol Browner issued guidance directing EPA to 

embrace the cumulative risk assessment approach on all future major risk 

assessments. Although directed to improve the environmental risk assessment 

process, EPA continues to rely on the outdated single chemical risk assessment 

approach, originally developed in 1954, to characterize the risk posed by 

perchlorate. The single chemical risk assessment approach fails to address 

known sources of scientific uncertainty, which lowers the confidence in the 

perchlorate RfD. 

Against established EPA risk assessment procedures, EPA derived the 

perchlorate RfD from a nonadverse biological effect instead of an adverse effect. 

The perchlorate RfD protects against all human biological effects from exposure, 

which is a stricter public health criterion than limiting environmental exposure to 

protect against adverse effects in humans. This shift in risk management 

constitutes a significant change in environmental policy. 

Based on our scientific analysis, perchlorate is only one of several chemicals that 

stress the thyroid’s ability to uptake iodide. The other sodium iodide symporter 

(NIS) stressors include thiocyanate, nitrate, and the lack of iodide. All four of 

these NIS stressors meet EPA’s risk assessment guidance for conducting a 

cumulative risk assessment using the dose-addition method. Our analysis 

implemented a cumulative risk assessment that found the following: 1) the risk 

from each of the four NIS stressors is not equal; 2) EPA’s perchlorate RfD is 

conservative and protective of human health, and further reducing the perchlorate 

exposure below the RfD does not effectively lower risk; 3) increasing maternal 

total iodide intake to healthy levels will reduce the frequency and severity of 

permanent mental deficits in children; and 4) correcting moderate and mild 

iodide deficiency occurring in about 29 percent of the U.S. pregnant and nursing 

population is the most effective approach for reducing risk. 
 

 

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY 

WASHINGTON, D.C. 20460 

OFFICE OF 

INSPECTOR GENERAL 

April 19, 2010 

MEMORANDUM 

SUBJECT:	 Office of Inspector General Scientific Analysis of Perchlorate 

 Report No. 10-P-0101 

FROM:	 Bill A. Roderick 

 Acting Inspector General 

TO: Lisa P. Jackson 

 Administrator 

The Office of the Inspector General (OIG) is providing this science report on our cumulative risk 

assessment of perchlorate and the other sodium (Na+)/iodide (I-) symporter stressors. This report 

represents the opinion of the OIG and does not necessarily represent the final position of the U.S. 

Environmental Protection Agency (EPA). EPA managers will make final determinations on 

matters in this report. This report contains no recommendations and no further action is required. 

The estimated cost of this report is $263,907. This amount incorporates both the OIG staff cost 

and the contracting cost for the technical review. The OIG staff cost is $214,322 and was 

calculated by multiplying the project’s staff days by the applicable daily full cost billing rates in 

effect at the time. The contracting cost for the technical review was $49,585. 

If you or your staff have any questions regarding this report, please contact me at 202-566-0847 or 

roderick.bill@epa.gov, or Eric Lewis at 202-566-2664 or lewis.eric@epa.gov. 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Office of Inspector General 10-P-0101 

Scientific Analysis of Perchlorate 

Table of Contents 

Section Page 

Executive Summary....................................................................................................... 1 

1 Defining the Public Health Issue .............................................................................. 10 

2 OIG’s Approach to the Scientific Analysis of Perchlorate ..................................... 14 

2.1 Introduction ....................................................................................................... 14 

2.2 Purpose............................................................................................................. 15 

2.3 Calls to Use Cumulative Risk Assessment ....................................................... 16 

2.4 Use of Mechanistic Toxicology.......................................................................... 19 

2.5 EPA Risk Assessment Procedures ................................................................... 20 

2.5.1 EPA Risk Assessment Guidance .......................................................... 20 

2.5.1.1 Applying the Dose-Addition Method .......................................... 21 

2.5.2 EPA Development of Cumulative Risk Assessments............................ 22 

2.6 Implementing a Cumulative Risk Assessment ................................................. 23 

2.6.1 Aspects in Implementing a Cumulative Risk Assessment..................... 24 

2.7 Summary of the OIG Approach......................................................................... 28 

3 Sodium (Na+

)/Iodide Symporter (NIS) Inhibitors ..................................................... 30 

3.1 Background ....................................................................................................... 30 

3.2 Relative Potencies of Other NIS Inhibitors........................................................ 30 

3.3 Human Thiocyanate Exposure.......................................................................... 31 

3.4 Human Nitrate Exposure................................................................................... 32 

3.5 Human Perchlorate Exposure ........................................................................... 33 

4 Modeling the NIS Stressors’ Influence on the Total Iodide Uptake (TIU) ............. 35 

4.1 Determining the Total NIS Inhibition Load Acting on the Human Body............. 35 

4.2 Serum Perchlorate Equivalant Concentration (SPEC)...................................... 35 

4.3 Oral Perchlorate Equivalent Concentration (OPEC) ........................................ 37 

4.4 Tonacchera NIS Model of Competitive Inhibition .............................................. 38 

5 Deriving a Reference Dose (RfD).............................................................................. 40 

5.1 Issues with the Single Chemical Risk Assessment of Perchlorate.................... 42 

5.1.1 Defining an RfD ..................................................................................... 42 

5.1.2 Evaluation of the Application of Uncertainty Factors (UF)
 

for Deriving the Perchlorate RfD............................................................ 45 

5.1.3 First Adverse Effect: Hypothyroidism or Hypothyroxinemia ................. 48 

5.1.4 Comparison of the NAS Unconventional RfD with a 

Conventionally Derived Excess NIS Inhibition RfD................................ 49 

5.1.4.1 Calculation of an Excess NIS Inhibition RfD Using 

the Adverse Thyroid Health Effects Observed in 

 Electroplating Workers Exposed to Cyanide in Adult Men......... 51 

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Office of Inspector General 10-P-0101 

Scientific Analysis of Perchlorate 

Table of Contents (continued) 

Section Page 

5.1.4.2 Calculation of an Excess NIS Inhibition RfD Using 

the Adverse Thyroid Health Effects from the Ingestion of 

 Thiocyanate-Preserved Cow’s Milk by Adult Women ................ 55 

5.1.4.3 Calculation of an Excess NIS Inhibition RfD Using 

the Adverse Effect Hypertrophy Observed in School-aged 

 Children Drinking Nitrate-Contaminated Drinking Water ........... 61 

6 Application of the Tonacchera Model to the Chilean Epidemiological Studies... 66 

6.1 Tellez Study ...................................................................................................... 66 

6.2 Crump Study ..................................................................................................... 75 

6.3 Conclusions....................................................................................................... 77 

7 Assessment of Total NIS Inhibitor Exposure .......................................................... 78 

7.1 Perchlorate Exposure........................................................................................ 78 

7.1.1 Adults .................................................................................................... 78 

7.1.2 Fetuses.................................................................................................. 80
 

7.1.3 Nursing Neonates.................................................................................. 81 

7.2 Total NIS Inhibitor Exposure ............................................................................. 83 

7.2.1 Total NIS Inhibition Load Acting on Adults ............................................ 83 

7.2.2 Total NIS Inhibition Load Acting on Fetuses ......................................... 87 

7.2.3 Total NIS Inhibition Load Acting on Nursing Infants.............................. 90 

7.2.4 Total NIS Inhibition Load Acting on Non-nursing Infants....................... 92 

8 Risk Characterization of NIS Stress ......................................................................... 94 

8.1 Hazard Characterization.................................................................................... 96 

8.2 Dose-Response Assessment............................................................................ 110 

8.3 Exposure Assessment....................................................................................... 116 

9 TIU Cumulative Risk Assessment ............................................................................ 129 

9.1 Corroboration of the Tonacchera Model with Effects Observed in Humans ..... 130
 

9.1.1 NAS Hypothyroidism Statement............................................................ 132
 

9.1.2 Hypothyroxinemia in Men Exposed to Excess Thiocyanate.................. 133 

9.1.3 Hypothyroxinemia in Women Exposed to Excess Thiocyanate ............ 136 

9.1.4 Perchlorate PBPK Model and the Greer Perchlorate Exposure Study.. 138
 

9.1.5 Braverman Perchlorate Occupational Exposure Study ......................... 145 

9.1.6 Qualitative Risk Assessment of NIS Stressors...................................... 148 

9.2 Assessing the Contribution of Each NIS Stressor on the TIU ........................... 152
 

9.2.1 Evaluation of the Amount of NIS Inhibition Contributed by 

 Each NIS Inhibitor ................................................................................. 152
 

9.2.2 Evaluation of %TIU as a Function of Total NIS Inhibition Load............. 153 

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Office of Inspector General 10-P-0101 

Scientific Analysis of Perchlorate 

Table of Contents (continued) 

Section Page 

9.2.3 Evaluation of the Role of Iodide Nutrition 

 on the Ability to Tolerate NIS Inhibition ................................................. 158 

9.2.4 Evaluation of the Relative Influence of Each NIS Stressor.................... 161
 

9.2.5 Assessing the Effectiveness of Lowering the Total 

 NIS Inhibition Load to Compensate for Poor Iodide Nutrition................ 163 

9.3 Application of UFs in a Multifactorial Cumulative Risk Assessment ................. 164 

9.4 Determining %TIU Levels of Concern .............................................................. 167 

9.4.1 Identifying a %TIU(LOAEL) in Pregnant Women 

 to Prevent Subtle Mental Deficits in Children ........................................ 167
 

9.4.2 Identifying a %TIU(NOAEL) in Pregnant Women 

 to Prevent Subtle Mental Deficits in Children ........................................ 168 

9.4.3 Identifying a %TIU(RfD) in Pregnant Women 

 to Prevent Subtle Mental Deficits in Children ........................................ 170 

9.5 Calculating the %TIU in Pregnant Women 

 at Various Perchlorate Exposures .................................................................... 172 

10 Approaches to Address this Public Health Issue ................................................. 175 

10.1 %TIU Exposure Levels of Concern ................................................................. 175
 

10.2 Remedy Approach........................................................................................... 175
 

10.2.1 Exposure Management of Each NIS Stressor..................................... 176
 

10.2.1.1 Lack of Iodide Stressor............................................................ 176 

10.2.1.1.1 Iodide Supplementation During Pregnancy 

 and Lactation ............................................................... 177 

10.2.1.1.2 Participation of the Medical Community ...................... 178 

10.2.1.2 Thiocyanate Stressor............................................................... 180 

10.2.1.3 Nitrate Stressor........................................................................ 181 

10.2.1.4 Perchlorate Stressor................................................................ 183 

11 Conclusion................................................................................................................ 185 

Appendices 

A “Whole Mixture” Approach to the Cumulative Risk Assessment of Perchlorate 

B References 

List of Acronyms and Abbreviations 

D Scientific Comments Received on the OIG Scientific Analysis of Perchlorate 

(External Review Draft) 

E OIG Response to Comments on OIG Scientific Analysis of Perchlorate 

(External Review Draft) 

F Distribution 

iii 

C 
10-P-0101 

Executive Summary 

Background 

Our science review evaluates the public health risk from the sodium (Na+

)/iodide (I-) 

symporter (NIS) stressors (e.g., perchorate) that can disrupt the uptake of iodide by the thyroid. 

The OIG Scientific Analysis of Perchlorate (the OIG Analysis) documents our review. The 

following is background information on perchlorate and other NIS stressors: 

•	 Perchlorate induces human toxicity by blocking the uptake of iodide into the thyroid. A 

protein called NIS mediates iodide transport from the blood into the thyroid. Since 

perchlorate acts to block the uptake of iodide, perchlorate is an NIS inhibitor. The 

perchlorate mechanism of toxicity is that excess perchlorate exposure lowers the total 

iodide uptake (TIU) of the thyroid. A prolonged low TIU decreases the supply of iodide 

in the thyroid and eventually results in the decreased production of thyroid hormones 

thyroxine (T4) and triiodothyronine (T3). Maintaining an adequate supply of maternal T4 

during pregnancy is critical for proper fetal brain development. A low TIU during 

pregnancy is associated with permanent mental deficits in the children of those mothers. 

The more severe the maternal TIU deficiency, the greater will be the frequency and 

severity of the permanent mental deficits in their children. 

•	 In addition to perchlorate, diet exposes humans to other NIS inhibitors that also lower the 

amount of iodide uptake by the thyroid. The other common dietary NIS inhibitors are 

thiocyanate and nitrate. All NIS inhibitors share the same mechanism of toxicity as 

perchlorate – blocking the uptake of iodide by the thyroid. 

•	 The risk to public health is from the combined amount of NIS inhibition acting on the 

body from all three NIS inhibitors (thiocyanate, nitrate, and perchlorate). This combined 

total NIS inhibition load acting on the thyroid determines the TIU level and the 

subsequent potential for an adverse outcome. The combined NIS inhibition load is 

known as the total goitrogen load. 

•	 In addition to NIS inhibitors, the amount of the essential dietary nutrient iodide directly 

affects the amount of iodide uptake by the thyroid in humans. For an environmental 

pollutant, increased exposure is associated with increased frequency and severity of 

adverse effect(s) on the body. Iodide, however, becomes an NIS stressor when there is an 

insufficient amount of iodide in the diet to allow for an adequate uptake of iodide by the 

thyroid. Therefore, the lack of iodide in the diet (i.e., iodide deficiency) is an NIS 

stressor and shares the same mechanism of toxicity as the NIS inhibitors – preventing the 

thyroid from taking up an adequate amount of iodide. Therefore, both the combined total 

NIS inhibition load acting on the thyroid and the iodide nutritional level determines the 

TIU level and the subsequent potential for an adverse outcome. 

•	 Diet continuously exposes all humans to all four NIS stressors (thiocyanate, nitrate, 

perchlorate, and iodide). Common vegetables in the diet are a significant and natural 

source of thiocyanate. Foods particularly rich in thiocyanate include cabbage, broccoli, 

1
 
 

10-P-0101 

Brussels sprouts, corn (maize), turnips, rapeseed, mustard seed, cauliflower, cabbage, 

radishes, spinach, tomatoes, and milk. Although diet is an important source of 

thiocyanate, cyanide produced and absorbed through cigarette smoking is also a 

significant source of thiocyanate. Nitrate is also common in food. Nitrate occurs in 

green leafy vegetables, is added to processed meats as a preservative, and is found in 

milk. In addition to dietary nitrate, both surface and ground sources of drinking water 

commonly contain nitrate due to the agricultural use of nitrate fertilizers. According to 

the Food and Drug Administration (FDA) Total Dietary Study, 46% to 59% of the total 

estimated intake of perchlorate comes from vegetables and dairy foods. Finally, the FDA 

Total Dietary Study also identifies dairy and grain as the most significant sources of 

dietary iodine for all groups of adults. Therefore, the degree of dietary exposure to each 

of the four NIS stressors (not just perchlorate) is needed to determine an individual’s TIU 

and the likelihood for an adverse outcome. 

•	 Other potential sources of perchlorate exposure are the Department of Defense/aerospace 

sector (e.g., rocket propellant), commercial products (i.e., safety flares and some 

fireworks (up to 70% content)), agricultural use (i.e., perchlorate is a contaminant in 

Chilean nitrate fertilizer (CNF)), and natural atmospheric production. The Department of 

Defense/aerospace sector accounts for about 90% of the annual U.S. consumption of 

perchlorate. The burning (i.e., use) of rocket propellants, safety flares, and perchloratecontaining fireworks does not result in a significant perchlorate exposure; 0.05% or less 

of the original perchlorate is left after use because the fire destroys the perchlorate. 

However, the improper disposal of unused rocket propellants, safety flares, and 

perchlorate containing fireworks allows the unused perchlorate to get into the 

groundwater and surface water, resulting in human perchlorate exposure upon ingestion 

of contaminated drinking water. Although this type of improper disposal into water 

sources would generate “hot spots” of perchlorate exposure within the population, “hot 

spots” would not generate the relatively uniform background of perchlorate exposure that 

is observed across the entire U.S. population. Natural production of perchlorate by the 

oxidation of chloride by lightning or ozone is not a significant source of drinking water 

contamination because rainfall contains a mean concentration of perchlorate of 0.015 

μg/L (max. 0.2 μg/L). 

In 2002, the U.S. Environmental Protection Agency (EPA) issued a draft perchlorate risk 

assessment titled Perchlorate Environmental Contamination: Toxicological Review and Risk 

Characterization (NCEA-1-1053) that proposed a perchlorate reference dose (RfD) of 0.00003 

milligram/kilogram-day (mg/kg-day). EPA’s proposed RfD corresponds to a drinking water 

equivalent level (DWEL) of 1 part per billion (ppb). EPA’s draft risk assessment relied 

primarily on a rat study conducted by Argus Research Laboratories in 2001. Due to the 

scientific controversy surrounding the concentration at which perchlorate should be regulated, 

EPA and others1

 charged the National Academy of Sciences (NAS) Committee to Assess the 

Health Implications of Perchlorate Ingestion (the NAS Committee) with assessing the current 

state of the science regarding potential adverse effects of disruption of thyroid function by 

perchlorate in humans and laboratory animals at various stages of life. Part of the NAS 

1

 The U.S. Department of Defense (DOD), U.S. Department of Energy (DOE), and the National Aeronautics and 

Space Administration (NASA). 

2
 
 

 

 

10-P-0101 

Committee’s charge was to determine whether EPA’s 2002 draft single chemical risk assessment 

of perchlorate was consistent with the current scientific evidence. In 2005, the NAS Committee 

rejected EPA’s approach of using the results from the Argus rat studies to derive the perchlorate 

RfD. 

In January 2005, the NAS Committee recommended an RfD of 0.0007 mg/kg-day based 

on the results observed in the Greer human perchlorate dose response study.2 The NAS 

Committee included a 10-fold uncertainty factor (UF) in the RfD to protect the most sensitive 

population, the fetuses of pregnant women who have hypothyroidism or iodide deficiency. On 

February 18, 2005, EPA established an RfD of 0.0007 mg/kg-day, which corresponds to a 

DWEL of 24.5 ppb. EPA is currently in the process of making a regulatory determination for 

perchlorate, which is a formal decision on whether to issue a National Primary Drinking Water 

Regulation. 

In the May 1, 2007, Federal Register (72 FR 24016), EPA indicated that it needed 

additional information on perchlorate exposure to determine a value for the relative source 

contribution of perchlorate. EPA must set a perchlorate relative source contribution value before 

it can make a regulatory determination on whether regulating perchlorate in drinking water 

presents a meaningful opportunity for health risk reduction. The relative source contribution will 

determine how much perchlorate exposure comes from food and water. 

Purpose of Science Review 

The OIG is frequently requested to examine the scientific support for a particular EPA 

decision or program action. Stakeholders often want an entity without a political or scientific 

bias to independently evaluate the scientific process and procedures used by the Agency. We 

believe there is a particular need for this type of independent review of regulatory toxicology. 

Generally, we have been unable to provide this service because we have a limited capacity to do 

this kind of work. Additionally, cutting edge science is many times a difficult subject to address. 

For this project, we had on staff a toxicologist with the requisite experience and training to 

deliver this service. 

In conducting this scientific analysis, we sought to use the state of the art techniques and 

to comply with EPA's risk assessment requirements so that the validity of our evaluation could 

be defended. We think we have done that. We expected to be challenged and we were. We 

believe we have responded fairly to all scientific comments and reached a reasonable conclusion. 

However, we know that other scientific entities will want to contest our findings. In our 

response to those organizations and people we explain why we think the data we used was valid 

and we identified the short comings of other data for use in an environmental risk assessment. 

Stakeholders should carefully consider all points before making a value judgment on the merits 

of this report. 

2

 The Greer study is a human perchlorate dose response study in which 37 male and female volunteers were given 

perchlorate in drinking water at 0.007, 0.02, 0.1, or 0.5 mg/kg-day for 14 days. The study results identified a noobserved-effect-level (NOEL) of 0.007 mg/kg-day. The NAS Committee used this NOEL value to derive its 

recommend perchlorate RfD. 

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10-P-0101 

The potential regulation of perchlorate in drinking water by EPA has been a contentious 

and divisive environmental issue. The congressional bills H.R. 1747 and S. 150, which would 

amend the Safe Drinking Water Act to require EPA to regulate perchlorate in drinking water, 

reflect the interest in addressing this public health issue. We analzyed the science supporting 

EPA’s perchlorate RfD. The completion of a human health risk assessment that derives a 

perchlorate RfD is a key element in the process of making a regulatory determination. Of 

particular concern is whether EPA’s perchlorate RfD is protective of human health at all life 

stages. Since EPA’s final perchlorate RfD is taken directly from the NAS Committee’s 

recommended perchlorate RfD of 0.0007mg/kg-day, we analyzed whether the NAS Committee’s 

recommended RfD is protective of human health at all life stages. Further, we evaluated the 

following scientific issues to assess the effectiveness of EPA’s risk assessment procedures: 

1.	 The NAS Committee used an unconventional approach to derive its recommended 

perchlorate RfD by using a no-effect-level, and asserted that this was a conservative, 

health-protective approach to the perchlorate risk assessment. 

2.	 The NAS Committee used a single UF of 10 for intraspecies variation to derive its 

recommended perchlorate RfD. The NAS Committee stated that its recommended 

perchlorate RfD needed no additional UFs. 

3.	 The NAS Committee stated that the first adverse effect of perchlorate is hypothyroidism. 

The Committee stated, “Defining the adverse effect is important because it influences 

how the RfD is derived and ultimately the value of the drinking-water standard.” 

4.	 EPA’s charge directed the NAS Committee to assess the potential adverse effects from 

perchlorate at various stages of life. The NAS Committee derived its recommended 

perchlorate RfD based on the TIU in healthy adults observed in the Greer study. 

However, since the scientific literature reports that the fetal thyroid is more sensitive to a 

deficiency in TIU. Therefore, an uncertainty to consider in addressing this public health 

issue is how well the adult thyroid response to perchlorate measured in the Greer study 

represents the fetal thyroid response to lack of an adequate TIU. 

5.	 The NAS Committee indicated that its recommended RfD is protective of the most 

sensitive population – “the fetuses of pregnant women who might have . . . iodide 

deficiency.” 

6.	 EPA’s charge to NAS is written in a single chemical risk assessment approach, which 

prevents the evaluation of the impact that the other dietary NIS inhibitors (i.e., 

thiocyanate and nitrate) have on this public health issue. 

7.	 EPA’s charge to NAS is written in a single chemical risk assessment approach, which 

prevents the evaluation of the impact that other NIS stressors, such as the lack of iodide, 

have on this public health issue. 

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10-P-0101 

Results of Review 

The OIG Analysis indicates that although EPA used a single chemical risk assessment for 

perchlorate, a cumulative risk assessment that assesses and characterizes the combined human 

health risk from all NIS stressors would better describe the nature and sources of risk affecting 

this public health issue. The major findings, which directly address each of seven scientific 

issues identified in the “Purpose” section of this report, are as follows. 

1. The NAS Committee’s Unconventional RfD Approach Is Conservative and 

Protective 

By applying the Tonacchera in vitro NIS Model of Competitive Inhibition in the OIG 

Analysis, we analyzed the NAS Committee’s statement that its unconventional approach of using 

a no-effect-level to derive its recommended RfD is both conservative and protective of human 

health. As with the NAS Committee, we could not utilize the conventional approach of deriving 

a perchlorate RfD because no perchlorate study has observed adverse effects in any human 

population. Therefore, we used the principles of cumulative risk and identified in the OIG 

Analysis that the other common dietary NIS inhibitors, thiocyanate and nitrate, act through the 

same mechanism of toxicity. The toxic levels observed in humans from excessive thiocyanate 

exposure allowed us to estimate a perchlorate RfD by converting the observed toxic NIS 

inhibition level for thiocyanate into a perchlorate equivalent concentration through the use of a 

relative potency factor. This allowed us to use the conventional risk assessment approach of 

deriving an RfD from a lowest-observed-adverse-effect-level by utilizing the adverse effect of 

hypothyroxinemia observed in women exposed to an excess NIS inhibition load caused by 

excessive thiocyanate exposure. When this decreased production of T4 observed in 

hypothyroxinemia occurs during pregnancy, subtle mental deficits occur in the offspring. 

Therefore, the decreased production of T4 during pregnancy is the same mechanism by which 

perchlorate’s NIS inhibition potentially causes mental damage during gestation and lactation. 

The OIG Analysis confirmed that the NAS-recommended perchlorate RfD is 

conservative by a factor of 6.6 times. In other words, a conventionally derived perchlorate RfD 

is 6.6 times higher than the NAS Committee’s recommended perchlorate RfD of 0.0007 mg/kgday. This finding supports the NAS Committee’s statement that its unconventional approach of 

deriving the perchlorate RfD represents a conservative value. However, the perchlorate RfD 

derived from a single chemical risk assessment approach is accurate only for those individuals 

with a typical background exposure to the other three NIS stressors. In other words, the 

perchlorate RfD is not a static value, but changes depending on the exposure level to the other 

three NIS stressors (thiocyanate, nitrate, and lack of iodide). 

2. Increasing Uncertainty Factors Do Not Effectively Protect Public Health 

The NAS Committee used a single UF of 10 for intraspecies variation to derive its 

recommended perchlorate RfD. EPA defines an RfD as a daily oral exposure likely to be 

without an appreciable risk of adverse health effects over a lifetime with uncertainty/variability 

factors applied to reflect limitations of the data used. In other words, the purpose of an RfD is to 

allow the setting of a regulatory exposure level that avoids the occurrence of adverse effect in 

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10-P-0101 

humans. The OIG Analysis identified that the use of UFs in a single chemical risk assessment is 

effective only if the chemical that the risk assessors are evaluating (i.e., perchlorate) is one of the 

principal agents inducing the adverse effect. We specifically evaluated the effectiveness of 

increasing the application of UFs in deriving the perchlorate RfD and measured the effect on 

preventing the TIU from becoming too low in pregnant women, fetuses, and nursing infants. We 

found that the scientific data indicate that perchlorate has the weakest impact of the four NIS 

stressors on the TIU. Lowering the perchlorate RfD has only a minimal effect on maintaining a 

TIU within a healthy range. The OIG Analysis identified that: 

•	 No increase in UF value derives a perchlorate RfD that is low enough to prevent mental 

damage in children, by itself. 

•	 In contrast, the only way to maintain a maternal TIU within a healthy range is to prevent 

the excessive exposure to each one of the four NIS stressors. 

•	 Limiting the exposure to perchlorate alone at or below the RfD cannot compensate for an 

excessive exposure to one or more of the other NIS stressors. 

3. Hypothyroxinemia Occurs Before Hypothyroidism 

As part of the OIG Analysis, we evaluated the NAS Committee statement that the first 

adverse effect of perchlorate is hypothyroidism. Hypothyroidism is a stressed thyroid condition 

characterized by a low free thyroxine (fT4) level with an elevated thyroid-stimulating hormone 

(TSH) level. The OIG Analysis of the scientific data found that the maternal thyroid’s initial 

response to a diminished uptake of iodide is not hypothyroidism but a less stressful thyroid 

condition called hypothyroxinemia (a low fT4 level with normal TSH level). Hypothyroxinemia 

is a common condition in pregnant women. Hypothyroxinemia reflects a thyroid condition in 

which the pregnant mother has difficulty meeting her own T4 needs and is unable to meet the 

fetal demand for T4, needed for proper brain development. We determined that 

hypothyroxinemia occurs in pregnant women when the TIU becomes less than or equal to 25% 

of normal. The OIG Analysis of the scientific data indicates that a maternal TIU equal to or less 

than 25% is associated with these effects in their children: 

•	 Attention-deficit/hyperactivity disorder (ADHD) 

•	 Lower verbal intelligence quotient (IQ) 

•	 Lower overall IQ 

•	 Lower motor performance 

The OIG Analysis of the scientific data estimated that up to 6.9% of infants (i.e., 276,000 infants 

per year) are born to U.S. mothers with maternal TIU of less than 25%. These children have a 

higher risk of suffering from these permanent subtle neurological, psychological, and intellectual 

deficits. This frequency of fetal exposure to maternal TIU of less than 25% is consistent with the 

estimated occurrence of attention-deficit/hyperactivity disorder (ADHD) at 19 years of age of 

7.5% (6.5% to 8.4% at a 95% confidence interval). 

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4. Low TIU Adversely Affects the Fetus First 

The EPA and others charged the NAS Committee to assess the potential adverse effects 

from perchlorate at various stages of life. The NAS Committee derived its recommended 

perchlorate RfD based on the TIU of healthy adults observed in Greer study. However, since the 

scientific literature indicates that the fetal thyroid is more sensitive to a deficiency in TIU, a 

scientific uncertainty to consider in addressing this public health issue is how well the adult 

thyroid response to perchlorate in the Greer study represents the fetal thyroid’s response to lack 

of an adequate TIU. The OIG Analysis of the scientific literature identified that the fetal thyroid 

is less able to adapt to a low TIU than the mother’s thyroid. Therefore, the first adverse effect 

occurs to the fetus before the mother’s thyroid performance shows any signs of stress (i.e., 

changes in thyroid hormone levels). Thus, risk assessors should use neither maternal 

hypothyroidism nor hypothyroxinemia as the key biological event in a risk assessment. By 

contrast, the first adverse effects in the fetus occur when the maternal TIU is between 25% and 

50% of normal. The OIG Analysis of the scientific data indicates that a maternal TIU between 

25% and 50% of normal is associated with these effects in their children: 

•	 Permanent delayed reaction time to stimuli 

•	 A higher frequency of elevated TSH in newborns (i.e., the cognitive impact of elevated 

TSH in newborns has not been studied) 

•	 An increased frequency of mild thyroid dysfunction (subclinical hypothyroidism) later in 

childhood (if born with elevated TSH levels) 

The OIG Analysis estimated that up to an additional 22% of infants (i.e., 880,000 infants per 

year) are being born to U.S. mothers with maternal TIU between 25% and 50%. 

5. Perchlorate RfD Alone Does Not Protect Most Sensitive Populations 

As part of the OIG Analysis, we evaluated the NAS Committee’s statement that its 

recommended perchlorate RfD is protective of the most sensitive population – “the fetuses of 

pregnant women who might have . . . iodide deficiency.” The OIG Analysis found that mild 

iodide deficiency decreases maternal TIU by 50% to 75%, while moderate iodide deficiency 

decreases maternal TIU by more than 75%. By contrast, the OIG Analysis calculated that 

decreasing the perchlorate exposure in drinking water from 24.5 ppb to 6.1 ppb would result in 

only a 1.0% increase in the maternal TIU. Clearly, a 1.0% increase in maternal TIU is 

insufficient to compensate for a 50% or more decrease in maternal TIU caused by mild to 

moderate iodide deficiency. Further, the OIG Analysis found that no amount of reduction in the 

body’s total NIS inhibition load (i.e., reducing the exposure to all three NIS inhibitors, not just 

perchlorate) is capable of compensating for mild or moderate iodide deficiency in humans. 

Iodide deficiency has a much stronger effect on lowering the maternal TIU than can be 

compensated for by reducing the environmental exposure to perchlorate and/or the other NIS 

inhibitors. Thus, to reduce the risk from this public health issue, mild and moderate iodide 

deficiency during pregnancy and nursing must be addressed. 

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6. Thiocyanate and Nitrate Must Be Included in the Risk Assessment 

The NAS charge prevented the NAS Committee from considering the impact of the other 

NIS inhibitors (i.e., thiocyanate and nitrate) on this public health issue. The OIG Analysis of the 

scientific literature identified that thiocyanate and nitrate have the same mechanism of toxicity as 

perchlorate. Therefore, thiocyanate and nitrate must be considered together in the risk 

assessment because their exclusion seriously distorts the portion of the total risk attributed to the 

principal stressor of concern, perchlorate. Although perchlorate is a strong NIS inhibitor, human 

exposure to perchlorate is relatively low so the contribution to the body’s total NIS inhibition 

load is relatively small. By contrast, although thiocyanate and nitrate are weak NIS inhibitors, 

their human exposure levels are much greater than perchlorate. Therefore, thiocyanate and 

nitrate account for the vast majority of the body’s typical total NIS inhibition load in adults, 

fetuses, and nursing infants. 

The OIG Analysis of the scientific data identified that the consumption of 2 liters of 

drinking water contaminated with nitrate at EPA’s maximum contaminant level induces 12 times 

the amount of NIS inhibition that perchlorate exposure at the RfD in an adult would cause. This 

indicates that lowering the nitrate exposure in drinking water is a more effective approach to 

increasing maternal TIU than lowering the perchlorate DWEL below 24.5 ppb. 

7. Lack of Iodide Is the Dominant NIS Stressor Affecting this Public Health Issue 

The NAS charge also prevented the NAS Committee from fully considering the role that 

iodide has on this public health issue. The OIG Analysis of the scientific literature identified that 

the lack of iodide is a nonchemical stressor that acts through the same mechanism of toxicity as 

perchlorate – limiting the TIU. The lack of iodide (a NIS stressor) has the same mechanism of 

toxicity as perchlorate and, therefore, must be included in the risk assessment because its 

exclusion seriously distorts the portion of the total risk attributed to the principal stressor of 

concern, perchlorate. The OIG Analysis found that the lack of iodide is the dominant and 

principal NIS stressor that determines a TIU level. 

The OIG Analysis of the scientific literature indicates that to reduce the frequency and 

severity of permanent mental deficits in children, the excessive exposure to each of the four NIS 

stressors is required to prevent low maternal TIU during pregnancy and nursing. Since 

thiocyanate, nitrate, and perchlorate are all chemicals, managing their exposure is within EPA’s 

legislative mandate. However, what would be the most effective action, overseeing the iodide 

nutrition level during pregnancy and lactation, is not in EPA’s legislative mandate. EPA’s 

Framework for Cumulative Risk Assessment directs EPA to seek expertise outside of the Agency 

to address aspects outside EPA authority. Therefore, EPA would have to work cooperatively 

with other federal agencies, such as the FDA and the National Institutes of Health, to safely 

correct low maternal TIU. To reduce the frequency and severity of permanent mental deficits in 

children from low maternal TIU, our cumulative risk assessment has identified adding iodide to 

prenatal vitamins and implementing their use before and during pregnancy and nursing as an 

approach to addressing this public health issue. 

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Conclusion 

The OIG Analysis of the scientific literature identified that the risk from perchlorate 

exposure is only part of a larger public health issue that is defined by the subtle mental deficits 

occurring in children born to mothers with low maternal TIU during pregnancy and nursing. The 

TIU results from the combined biological effect of four NIS stressors acting on the thyroid: 

thiocyanate, nitrate, perchlorate, and lack of iodide. Diet constantly exposes everyone to each of 

the four NIS stressors, and an individual’s TIU level is the result of the combined effect of all 

four NIS stressors, not just perchlorate exposure. The OIG Analysis concludes that a single 

chemical risk assessment of perchlorate is not sufficient to assess and characterize the combined 

human health risk from all four NIS stressors. However, both EPA’s draft perchlorate RfD from 

the Argus rat study and the NAS Committee’s recommended perchlorate RfD from the Greer 

study used a single chemical risk assessment approach. Only a cumulative risk assessment can 

fully characterize the nature and sources of risk affecting this public health issue. Furthermore, a 

cumulative risk assessment allows an informed environmental decision to be made on how to 

mitigate the risk effectively 

All four NIS stressors meet EPA’s risk assessment guidance requirements for conducting 

a cumulative risk assessment using the dose-addition method. In the OIG Analysis, we 

conducted a cumulative risk assessment and determined that the risk from each of the four NIS 

stressors is not equal. The OIG Analysis also confirmed that EPA’s perchlorate RfD is 

conservative and protective of human health, but limiting perchlorate exposure does not 

effectively address this public health issue. Potentially lowering the perchlorate drinking water 

limit from 24.5 ppb to 6 ppb does not provide a meaningful opportunity to lower the public’s 

risk. By contrast, addressing moderate and mild iodide deficiency occurring in about 29% of the 

U.S. pregnant and nursing population appears to be the most effective approach to increase TIU 

to healthy levels during pregnancy and nursing, thereby reducing the frequency and severity of 

permanent mental deficits in children. 

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1. Defining the Public Health Issue 

Background 

Perchlorate induces human toxicity by blocking the uptake of iodide into the thyroid. A 

protein called the sodium (Na+)/iodide (I-) symporter (NIS) mediates iodide transport from the 

blood into the thyroid. Since perchlorate acts to block the uptake of iodide, perchlorate is an NIS 

inhibitor. The perchlorate mechanism of toxicity is that excess perchlorate exposure lowers the 

total iodide uptake (TIU) of the thyroid. A prolonged low TIU decreases the supply of iodide in 

the thyroid and eventually results in decreased production of thyroid hormones thyroxine (T4) 

and triiodothyronine (T3). Maintaining an adequate supply of maternal T4 during pregnancy is 

critical for proper fetal brain development. A low TIU during pregnancy is associated with 

permanent mental deficits in the children of those mothers. The more severe the maternal TIU 

deficiency, the greater will be the frequency and severity of the permanent mental deficits in 

their children. 

In addition to perchlorate, diet exposes humans to other NIS inhibitors that also lower the 

amount of iodide uptake by the thyroid in humans. The other common dietary NIS inhibitors are 

thiocyanate and nitrate. All NIS inhibitors share the same mechanism of toxicity as perchlorate – 

blocking the uptake of iodide by the thyroid. The risk to public health is from the combined 

amount of NIS inhibition acting on the body from all three NIS inhibitors (thiocyanate, nitrate, 

and perchlorate). This combined total NIS inhibition load acting on the thyroid determines the 

TIU level and the subsequent potential for an adverse outcome. The combined NIS inhibition 

load is known as the total goitrogen load. 

In addition to NIS inhibitors, the amount of the essential nutrient iodide in the diet 

directly affects the amount of iodide uptake by the thyroid in humans. Unlike an environmental 

pollutant where increased exposure is associated with increased frequency and severity of 

adverse effect(s) on the body, iodide becomes an NIS stressor when there is an insufficient 

amount of iodide in the diet to allow for an adequate uptake of iodide by the thyroid. Therefore, 

the lack of iodide in the diet (i.e., an iodide deficiency) is an NIS stressor and shares the same 

mechanism of toxicity as the NIS inhibitors – preventing the NIS from taking up an adequate 

amount of iodide. Therefore, both the combined total NIS inhibition load acting on the thyroid 

and the iodide nutritional level determines the TIU level and the subsequent potential for an 

adverse outcome. 

Diet continually exposes all humans to all four NIS stressors (thiocyanate, nitrate, 

perchlorate, and iodide). Vegetables are a significant and natural source of thiocyanate. Foods 

particularly rich in thiocyanate include cabbage, broccoli, Brussels sprouts, corn (maize), turnips, 

rapeseed, mustard seed, cauliflower, cabbage, radishes, spinach, tomatoes, and milk. Although 

diet is an important source of thiocyanate, cyanide produced and absorbed through cigarette 

smoking is also a significant source of thiocyanate. Nitrate is also common in food. Nitrate 

occurs in green leafy vegetables, is added to processed meats as a preservative, and is found in 

milk. In addition to dietary nitrate, both surface and ground sources of drinking water commonly 

contain nitrate due to the agricultural use of nitrate fertilizers. According to the Food and Drug 

Administration (FDA) Total Dietary Study (TDS), 46% to 59% of the total estimated intake of 

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perchlorate comes from vegetables and dairy foods. Finally, the FDA TDS also identifies dairy 

and grain as the most significant sources of dietary iodine for all groups of adults. Therefore, 

the degree of dietary exposure to each of the four NIS stressors (not just perchlorate) is needed to 

determine an individual’s TIU and the likelihood for an adverse outcome. 

In 2002, the U.S. Environmental Protection Agency (EPA) issued a draft perchlorate risk 

assessment titled Perchlorate Environmental Contamination: Toxicological Review and Risk 

Characterization (NCEA-1-1053) that proposed a perchlorate reference dose (RfD) of 0.00003 

milligram/kilogram-day (mg/kg-day). EPA’s proposed RfD corresponds to a drinking water 

equivalent level (DWEL) of 1 ppb. EPA’s draft risk assessment relied primarily on a rat study 

conducted by Argus Research Laboratories in 2001. Due to the scientific controversy 

surrounding the concentration at which perchlorate should be regulated, the National Academy 

of Science (NAS) Committee to Assess the Health Implications of Perchlorate Ingestion (NAS 

Committee) was charged to assess the current state of the science regarding potential adverse 

effects of thyroid function disruption by perchlorate in humans and laboratory animals at various 

stages of life. Part of the NAS Committee’s charge was to determine whether EPA’s 2002 draft 

single chemical risk assessment of perchlorate was consistent with the current scientific 

evidence. In 2005, the NAS Committee rejected EPA’s approach of using the Argus rat studies 

to derive the perchlorate RfD. 

In January 2005, the NAS Committee recommended an RfD of 0.0007 mg/kg-day based 

on the results observed in the Greer human perchlorate exposure study. The NAS Committee 

included a 10-fold uncertainty (UF) in the RfD to protect the most sensitive population, the 

fetuses of pregnant women who have hypothyroidism or iodide deficiency. On February 18, 

2005, EPA established an RfD of 0.0007 mg/kg-day, which corresponds to a DWEL of 24.5 

ppb. EPA is currently in the process of making a regulatory determination for perchlorate, which 

is a formal decision on whether to issue a National Primary Drinking Water Regulation. 

In the May 1, 2007, Federal Register (72 FR 24016), EPA indicated that it needed 

additional information on perchlorate exposure to determine a value for the Relative Source 

Contribution of perchlorate. EPA must set a perchlorate Relative Source Contribution value 

before it can make a regulatory determination on whether regulating perchlorate in drinking 

water presents a meaningful opportunity for health risk reduction. The Relative Source 

Contribution will determine how much perchlorate exposure comes from food and water. 

Utilizing Cumulative Risk Assessment. In 2005, the NAS Committee reviewed the 

current state of the science regarding the potential adverse health effects of perchlorate exposure 

(NAS 2005). The charge to the NAS Committee limited the context of its assessment to the 

potential adverse effects from perchlorate only. This approach to assess the toxicity of a single 

chemical is an outdated, conventional approach to characterizing the risk to the public. By 

contrast, the state-of-the-art technique to assess risk is to perform a cumulative risk assessment 

when multiple chemicals or stressors act through the same mechanism of toxicity. As indicated 

by former EPA Administrator Browner in 1997, cumulative risk assessment “provides a platform 

for significant advances in our scientific approach to assessing environmental risks” (EPA 

1997b). 

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Recent Perchlorate Studies Have Different Conclusions. Various published 

perchlorate studies draw substantially different conclusions on the toxicity of perchlorate. 

•	 The Argus 2001 rat study and the Blount 2006 urinary perchlorate study suggest the 

need for a lower RfD. Based principally on the observations made in the Argus 2001 

rat study (Argus 2001), in 2002 the EPA proposed a perchlorate RfD of 0.00003 

mg/kg-day, which corresponds to a DWEL of 1 ppb (EPA 2002a). 

•	 The Blount 2006 urinary perchlorate study observed that increased urinary 

perchlorate was associated with increased thyroid-stimulating hormone (TSH) and 

decreased T4 levels in women with iodide deficiency (i.e., urinary iodide levels less 

than 100 μg/L) (Blount 2006b). 

•	 By contrast, based on the perchlorate dosing of humans in the Greer study (Greer 

2002), the NAS Committee proposed a perchlorate RfD of 0.007 mg/kg-day, which 

corresponds to a DWEL of 24.5 ppb (NAS 2005). 

•	 The Tellez 2005 study of pregnant women and neonates in Taltal, Chile, which are 

exposed to drinking water at 114 ppb, are observed to have no statistically significant 

changes in neonatal thyroid function or birth weight (Tellez 2005). 

The lack of agreement in the perceived toxicity of perchlorate among these studies 

indicates that there is still an unacceptable level of uncertainty in the science of perchlorate to 

instill confidence that the current EPA perchlorate RfD is protective of human health. 

Cumulative Risk Assessment is Possible. Perchlorate is not the only anion acting on the 

thyroid to inhibit the uptake of iodide by the NIS. Humans are exposed nutritionally and 

environmentally to NIS inhibitors other than perchlorate that also inhibit the uptake of iodide by 

the NIS. 

•	 The other principal NIS inhibitors of concern to humans are thiocyanate (SCN-

) and 

nitrate (NO3

-

). 

•	 Furthermore, since iodine is the signature element in the molecular structure of the 

two thyroid hormones, T4 and T3, a sufficient supply of iodide in the diet is essential 

for the thyroid to be able to synthesize an adequate supply of thyroid hormones to the 

body. 

These three additional factors involved in the uptake of iodide are known and often cited 

in the scientific literature, but their relative contribution to the uptake of iodide has not been 

quantified or used in either EPA’s or the NAS Committee’s risk characterization. However, to 

reduce the uncertainties in the science, the relative contributions of each of the four factors (i.e., 

thiocyanate, nitrate, perchlorate, and the lack of iodide in the diet) to the uptake of iodide must 

be quantified and included in the risk assessment before making any effective environmental risk 

management decisions. The Tonacchera in vitro NIS Model of Competitive Inhibition 

(Tonacchera Model) quantified the relationship to the uptake of iodide from each of these four 

factors (Tonacchera 2004). The Tonacchera Model provides the critical information upon which 

to conduct a state-of-the-art cumulative risk assessment for this public health issue. 

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Summary. The EPA and NAS Committee approach to characterizing the risk from 

perchlorate suggests that the public health issue is driven by perchlorate only. This approach 

implies that the proposed remedy of lowering the exposure to perchlorate also directly lowers the 

risk to the public. In other words, if the perchlorate level is lowered to a “safe” level, the public 

health issue is eliminated. However, this single chemical approach and remedy underestimates 

the complexity of the public health issue. The actual occurrence of an adverse outcome is 

determined by the combined interaction of all four factors on the uptake of iodide by the NIS. 

For EPA and the NAS Committee to determine the risk from just one factor without knowing or 

managing the risk from the other three factors inadequately captures the amount of risk to the 

public. Further, managing only the risk from perchlorate will not effectively address the public 

health issue because the OIG Analysis shows that perchlorate contributes the least amount of risk 

of the four factors. Therefore, the public health issue must be defined beyond just perchlorate. 

The public health issue must consider and address all factors that prevent an adequate supply of 

thyroid hormones during gestation and lactation to ensure proper brain development in both 

fetuses and nursing infants. All the factors that impact the adequate supply of thyroid hormones 

must be quantitatively evaluated in a cumulative risk assessment. The use of cumulative risk 

assessment allows the relative contribution of risk from each factor to be identified and an 

effective and cost-efficient solution to be determined. 

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2. OIG’s Approach to the Scientific Analysis of Perchlorate 

2.1 Introduction 

Our science review identified and focused on scientific issues associated with the setting 

of the perchlorate RfD, which is a key element in the process of making a regulatory 

determination for perchlorate. We focused on the scientific process from EPA’s issuance of the 

2002 draft perchlorate risk assessment, Perchlorate Environmental Contamination: 

Toxicological Review and Risk Characterization, to July 2008. We conducted field work from 

April 2007 to July 2008. The OIG Scientific Analysis of Perchlorate (External Review Draft) 

(the OIG Analysis) documents our science review. The OIG Analysis cites approximately 145 

scientific journals as well as technical references and EPA risk assessment guidance. 

The OIG Analysis identified that a single chemical risk assessment determines the risk to 

a defined population to the exposure of a single chemical from all routes of exposure (e.g., air, 

water, soil, food, etc.). By contrast, a cumulative risk assessment is an analysis, characterization, 

and quantification of the combined risks to health from exposure to multiple chemicals or 

stressors. Since 1992, experts in the scientific community, the National Academy of Sciences, 

the President, Congress, and former EPA Administrator Browner have either identified the need 

or directed EPA to use a cumulative risk assessment approach to assess the risk to public health 

from exposure to environmental contaminations. Therefore, our OIG Analysis applied a 

cumulative risk assessment approach to evaluate the public health risk from exposure to 

perchlorate and the other NIS stressors. 

We implemented a cumulative risk assessment by following the concepts in EPA’s 

Framework for Cumulative Risk Assessment (EPA/600/P-02/001F) and the principle of dose 

addition described in EPA’s risk assessment guidance for chemical mixtures. Further, we used 

the NAS Committee on Toxicity Testing and Assessment of Environmental Agents (NAS 

Toxicity Testing Committee) recommendation for the development of a quantitative, 

mechanistic, dose-response model of the cellular pathway that is perturbed by the environmental 

agent. We implemented the NAS Toxicity Testing Committee’s vision and strategy by applying 

the Tonacchera Model to evaluate the cumulative public health risk from perchlorate and the 

other NIS stressors. Therefore, we conducted a cumulative risk assessment on this public health 

issue defined as low TIU during pregnancy and lactation. 

The Agency’s Peer Review policy encourages and expects all scientific and technical 

information intended to inform or support Agency decision making (i.e., rulemaking) to be peer 

reviewed. Specifically, “influential scientific information” and “highly influential scientific 

assessments” should be peer reviewed in accordance with the Agency’s Peer Review Handbook 

(EPA 2006). Since the OIG does not conduct rulemaking, the OIG Analysis did not undergo a 

formal peer review. However, the OIG Analysis did undergo an independent, third-party 

technical review. Four senior scientists from ICF International with direct knowledge and 

experience in environmental risk assessment reviewed and provided comments on a working 

draft of the OIG Scientific Analysis of Perchlorate. The purpose of this technical review was for 

the OIG to get an independent scientific critique of our application of a cumulative risk 

assessment to this public health issue induced by a low TIU during pregnancy and lactation. In 

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short, ICF International supported the implementation of a cumulative risk assessment, but 

recommended using the whole mixture cumulative risk assessment approach as opposed to the 

dose-addition method cumulative risk assessment approach. The OIG Analysis addresses the 

whole mixture approach to the cumulative risk assessment of perchlorate in Appendix A. 

However, in discussions with ICF International, the lead ICF scientist concurred that the 

biochemical properties and mechanistic interaction of the four NIS stressors meet all the EPA 

risk assessment requirements for the use of the dose-addition method (see Section 2.5.1.1). 

2.2 Purpose 

The OIG is frequently requested to examine the scientific support for a particular EPA 

decision or program action. Stakeholders often want an entity without a political or scientific 

bias to independently evaluate the scientific process and procedures used by the Agency. We 

believe there is a particular need for this type of independent review of regulatory toxicology. 

Generally, we have been unable to provide this service because we have a limited capacity to do 

this kind of work. Additionally, cutting edge science is many times a difficult subject to address. 

For this project, we had on staff a toxicologist with the requisite experience and training to 

deliver this service. 

In conducting this scientific analysis, we sought to use the state of the art techniques and 

to comply with EPA's risk assessment requirements so that the validity of our evaluation could 

be defended. We think we have done that. We expected to be challenged and we were. We 

believe we have responded fairly to all scientific comments and reached a reasonable conclusion. 

However, we know that other scientific entities will want to contest our findings. In our 

response to those organizations and people we explain why we think the data we used was valid 

and we identified the short comings of other data for use in an environmental risk assessment. 

Stakeholders should carefully consider all points before making a value judgment on the merits 

of this report. 

EPA’s potential regulation of perchlorate in drinking water has been a contentious and 

divisive environmental issue. The congressional bills H.R. 1747 and S. 150, which would amend 

the Safe Drinking Water Act to require EPA to regulate perchlorate in drinking water, reflects 

the interest in addressing this public health issue. We reviewed EPA’s procedures over its 

regulatory determination process for perchlorate. The completion of a human health risk 

assessment that derives a perchlorate RfD is a key element in the process of making a regulatory 

determination. Of particular concern is whether EPA’s perchlorate RfD is protective of human 

health at all life stages. Since EPA’s final perchlorate RfD is taken directly from the NAS 

Committee’s recommended perchlorate RfD of 0.0007mg/kg-day, we analzyed whether the NAS 

Committee’s recommended RfD is protective of human health at all life stages. Further, we 

analyzed the following scientific issues to assess the effectiveness of EPA’s risk assessment 

procedures: 

•	 The NAS Committee used an unconventional approach to derive its recommended 

perchlorate RfD by using a no-effect-level and asserted that this was a conservative, 

health-protective approach to the perchlorate risk assessment. 

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•	 The NAS Committee used a single UF of 10 for intraspecies variation to derive its 

recommended perchlorate RfD. The NAS Committee stated that its recommended 

perchlorate RfD needed no additional UFs. 

•	 The NAS Committee stated that the first adverse effect of perchlorate is hypothyroidism. 

The Committee stated, “Defining the adverse effect is important because it influences 

how the RfD is derived and ultimately the value of the drinking-water standard.” 

•	 EPA’s charge directed the NAS Committee to assess the potential adverse effects from 

perchlorate at various stages of life. The NAS Committee derived its recommended 

perchlorate RfD based on the TIU in healthy adults observed in the Greer study. 

However, since the scientific literature reports that the fetal thyroid is more sensitive to a 

deficiency in TIU, an uncertainty to consider in addressing this public health issue is how 

well the adult thyroid response to perchlorate measured in the Greer study represents the 

fetal thyroid response to lack of an adequate TIU. 

•	 The NAS Committee indicates that its recommended RfD is protective of the most 

sensitive population, “the fetuses of pregnant women who might have . . . iodide 

deficiency.” 

•	 EPA’s charge to NAS is written in a single chemical risk assessment approach, which 

prevents the evaluation of the impact that the other dietary NIS inhibitors (i.e., 

thiocyanate and nitrate) have on this public health issue. 

•	 EPA’s charge to NAS is written in a single chemical risk assessment approach, which 

prevents the evaluation of the impact that other NIS stressors, such as the lack of iodide, 

have on this public health issue. 

To address these scientific issues, the OIG Analysis applies both mechanistic toxicology and a 

cumulative risk assessment to this public health issue. 

2.3 Calls to Use Cumulative Risk Assessment 

We identified that the EPA draft 2002 perchlorate risk assessment, Perchlorate 

Environmental Contamination: Toxicological Review and Risk Characterization (NCEA-1­

1053), used a single chemical risk assessment approach to a proposed perchlorate RfD of 

0.00003 mg/kg-day (corresponding to a DWEL of 1 ppb). Furthermore, we found that the NAS 

Committee also used a single chemical risk assessment approach to recommend a perchlorate 

RfD of 0.0007 mg/kg-day (corresponding to a DWEL of 24.5 ppb). Therefore, both EPA and the 

NAS Committee used a single chemical risk assessment approach to derive their respective 

perchlorate RfDs. However, since as early as 1992, EPA has known that a single chemical risk 

assessment is an outdated approach to assessing risk. A single chemical risk assessment 

characterizes the potential adverse effect and quantifies the risk from only a single chemical 

pollutant; it does not evaluate the combined effects from multiple chemicals acting through the 

same mechanism of toxicity. 

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By contrast, a cumulative risk assessment is defined as “an analysis, characterization, and 

possible quantification of the combined risks to health or the environment from multiple agents 

or stressors” (EPA 2003, p 6). The application of a cumulative risk assessment has the potential 

to expand our understanding of the public health impacts of environmental exposures and 

provides a clearer, more complete picture of a public health issue for making risk management 

decisions. In 1995, former EPA Administrator Browner stated, “EPA must be responsive and 

resolve to more openly and fully communicate to the public the complexities and challenges of 

environmental decision making in the face of scientific uncertainty” (Callahan 2007). In 1997, 

then-Administrator Browner wrote that a cumulative risk assessment “provides a platform for 

significant advances in our scientific approach to assessing environmental risks.” Furthermore, 

cumulative risk assessments can reduce risks to the extent that EPA can integrate it into 

prevention strategies to protect public health. 

Experts in the scientific community, various NAS committees, the Science Advisory 

Board (SAB), the President, Congress, and former EPA Administrator Browner either have 

identified the need or directed EPA to use a cumulative risk assessment approach to assess the 

risk to public health from the exposure to environmental contamination: 

•	 The 1992 Expert Panel on the Role of Science at EPA issued the report titled 

Safeguarding the Future: Credible Science, Credible Decisions (EPA/600/9-91/050). 

The reported pointed out, “A key role of science at EPA is to reduce uncertainties in 

environmental decision-making.” One of the uncertainties identified by the 1992 

Expert Panel that needed to be addressed was the “ . . . impact of chemical mixtures 

and other general stressors [on people and the ecosystem] . . . ” (EPA 1992, p 14). 

However, the 1992 Expert Panel noted that EPA has not developed methods to assess 

the health or environmental effects from multiple stressors (EPA 1992, p 14). 

•	 In 1994, the NAS Committee on Risk Assessment of Hazardous Air Pollutants issued 

Science and Judgment in Risk Assessment, which recommended that EPA move away 

from single-chemical assessments and to aggregate cancer risks from exposure to 

multiple compounds (NAS 1994, executive summary 13; EPA 2000, p x (first 

bullet)). 

•	 Under Section 3-301(b), Presidential Executive Order 12898 (1994) directs federal 

agencies to identify “multiple and cumulative exposures” in environmental human 

health analyses, whenever practicable and appropriate. 

•	 In 1996, Congress mandated, under Section 408(b)(2)(C)(i)(III) of the Food Quality 

Protection Act of 1996, that EPA assess the cumulative risk to children and infants 

from pesticide chemical residues and other substances having a “common mechanism 

of toxicity”. 

•	 In 1997, former EPA Administrator Browner directed the Agency “to take into 

account cumulative risk issues in scoping and planning major risk assessments and to 

consider a broader scope that integrates multiple sources, effects, pathways, stressors, 

and populations for cumulative risk analysis in all cases for which relevant data are 

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available” and to “embrace this cumulative approach” in all major risks assessments 

(EPA 1997b). 

•	 In 1997, the EPA Science Policy Council stated EPA risk assessments should evolve 

away from a focus on the potential adverse effect of a single pollutant in one 

environmental medium. 

•	 In 2007, EPA’s Office of the Science Advisor requested SAB to provide 

recommendations on ways to advance EPA’s human health risk assessment practices. 

On February 28, 2007, SAB recommended to advance cumulative risk assessment 

methodologies in order to reflect real-world human exposure that includes multiple 

stressors (SAB 2007). 

•	 In 2008, the NAS Committee on Improving Risk Analysis Approaches Used by the 

U.S. EPA issued Science and Decisions: Advancing Risk Assessment, which 

recommended that EPA “ . . . incorporate interactions between chemical and 

nonchemical stressors in assessments” (NAS 2008; executive summary, p 9). This 

NAS Committee stated, “EPA is increasingly asked to address broader public-health 

and environmental-health questions involving multiple exposures, complex mixtures, 

and vulnerability of exposed populations issues that stakeholder groups . . . often 

consider to be inadequately captured by current risk assessments. There is a need for 

cumulative risk assessments as defined by EPA (EPA 2003)—assessments that 

include combined risks posed by aggregate exposure to multiple agents or 

stressors . . . ” ((NAS 2008; executive summary, p 9). 

•	 In 2008, the SAB Drinking Water Committee in its draft report on the Third 

Drinking Water Contaminant Candidate List (CCL3) (December 3, 2008) proposes 

recommending that “EPA should consider addressing the cumulative effects of 

chemicals with similar sources and mechanisms (or modes) of action . . . ” 

(SAB 2008). 

In contrast to a single chemical risk assessment approach previously used by both EPA 

and the NAS Committee to characterize the risk from perchlorate, a cumulative risk assessment 

approach better evaluates the public health risk from exposure to perchlorate and the other NIS 

stressors. The toxicity pathway identifies that an inadequate supply of iodide (i.e., low TIU) 

during gestation and possibly during lactation results in increased risk for subtle mental deficits 

in children. Perchlorate is only one of four NIS stressors (thiocyanate, nitrate, perchlorate, and 

lack of iodide) that act on the NIS to lower the TIU by the thyroid. The human diet contains all 

four NIS stressors; diet universally exposes every human to each of the four NIS stressors. 

Therefore, an individual’s TIU level is the combined effect of all four NIS stressors, not just 

perchlorate exposure. Since a low maternal TIU results in an increased risk for an adverse 

outcome, EPA should evaluate, through a cumulative risk assessment, the relative contribution 

that each NIS stressor has on inducing a low TIU. The findings from the cumulative risk 

assessment produce a broader, more comprehensive understanding and assessment of the factors 

involved in this public health issue. 

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2.4 Use of Mechanistic Toxicology 

On June 12, 2007, the NAS Toxicity Testing Committee released a report titled Toxicity 

Testing in the Twenty-First Century: A Vision and A Strategy (NAS 2007). The NAS Toxicity 

Testing Committee recommended a major shift in how the toxicity of chemicals is assessed 

because of the revolutionary advances in the science (e.g., proteomics, genomics, and 

biochemistry) in which the increased understanding of the biological mechanisms allows in vitro 

toxicity testing to be applied to environmental risk assessments. The NAS Toxicity Testing 

Committee’s vision is to move away from the traditional descriptive animal toxicity testing to the 

identification of perturbed biological pathways as the basis for dose-response modeling. Classic 

descriptive animal toxicity testing determines a dose in which no adverse effects are identified. 

Descriptive toxicity testing does not develop an understanding or a characterization of the 

cellular mechanism triggering the toxicity. The NAS Toxicity Testing Committee’s vision of 

toxicity testing is to develop a quantitative, mechanistic, dose-response model of the cellular 

pathway that is perturbed by the environmental agent. Subsequent pharmacokinetic modeling 

would identify a safe human exposure level that prevents the environmental chemical from 

reaching a toxic tissue concentration. The NAS Toxicity Testing Committee states, “A stronger 

scientific foundation offers the prospect of improved risk-based regulatory decisions and 

possibly greater public confidence in and acceptance of the decisions.” 

The NAS Toxicity Testing Committee’s vision can be observed in the evolving 

perchlorate science. In 2002, EPA released the draft risk assessment Perchlorate Environmental 

Contamination: Toxicological Review and Risk Characterization, which proposed a perchlorate 

RfD of 0.00003 mg/kg-day. EPA’s risk assessment relied on observations made in two rat 

studies conducted by Argus Research Laboratories in 1998 and 2001. These studies are 

examples of classic descriptive toxicity testing in which various perchlorate doses are evaluated 

for their potential to produce adverse effects (e.g., brain structural changes) in the most sensitive 

population – pregnant females, fetuses, and neonates. Although the lack of thyroid hormones 

during early development can lead to brain damage, these rat studies were not designed to 

identify or study a specific cellular pathway that is impacted by perchlorate exposure. These 

studies were also not designed to develop a quantitative, mechanistic, dose-response model of 

the perturbed cellular pathway that could have led to the observed changes in the linear 

measurements of several brain regions of the male and female pups (e.g., corpus callosum). 

In 2005, the NAS Committee to Assess the Health Implications of Perchlorate Ingestion 

was charged to review EPA’s 2002 draft perchlorate risk assessment. The NAS Committee 

found that it was impossible to conclude whether perchlorate exposure caused these brain 

changes because of problems with the method used to make the measurements, and because the 

observed changes did not follow a dose-effect relationship. The NAS Committee proposed a 

mechanistic step (i.e., a perturbation of a cellular pathway) that initiates a sequence of 

subsequent biological events that eventually results in adverse effects in humans. The key 

cellular event identified was perchlorate inhibiting the NIS, resulting in the decreased uptake of 

iodide by the thyroid’s epithelial cells. The NAS Committee used only the inhibitory effect of 

perchlorate on this cellular step as the basis to derive a recommended perchlorate RfD. The 

evaluation of only perchlorate’s inhibition does not represent a quantitative, dose-response model 

of the prominent factors (i.e., iodide, thiocyanate, nitrate, and perchlorate) that impact the uptake 

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of iodide by the NIS. The NAS Committee relied primarily on the Greer study to develop its 

recommended perchlorate RfD of 0.0007 mg/kg-day. The Greer study applied descriptive 

toxicity testing techniques to develop a dose-response curve in order to identify a perchlorate 

dose in human test subjects that did not inhibit the uptake of iodide by the NIS. The NAS 

Committee’s recommended perchlorate RfD was not based on a quantitative, dose-response 

model of the prominent factors that impact the uptake of iodide by the NIS. The NAS 

Committee used a single chemical risk assessment approach despite the fact that the uptake of 

iodide by the NIS was known to be perturbed by other NIS inhibitors and to be affected by the 

amount of available iodide in the blood. 

OIG’s approach to reviewing the perchlorate science is consistent with the NAS Toxicity 

Testing Committee’s vision and strategy for toxicity testing and its implications on risk 

assessment. In 2004, Tonacchera developed and evaluated an in vitro NIS Model of Competitive 

Inhibition (Tonacchera 2004). This model quantitatively determines the dose-response of the 

NIS to the presence of all of the following four anions simultaneously: thiocyanate, nitrate, 

perchlorate, and iodide. The model predicts the thyroidal iodide uptake by correlating the 

amount of iodide (i.e., iodide nutritional status) for any given total NIS inhibitor load (i.e., total 

goitrogen load). The Tonacchera Model quantifies the total goitrogen load into a single value by 

mathematically combining the amount of inhibition contributed from thiocyanate, nitrate, and 

perchlorate by using potency factors. Tonacchera developed the model from in vitro 

experiments that exposed Chinese hamster ovary (CHO) cells expressing the human NIS protein 

to various combinations of the four anions and measured the amount of uptake of radioactive 

iodide by the cells. The use of the Tonacchera Model for human health risk assessment 

implements the NAS Toxicity Testing Committee’s vision of toxicity testing by using a 

quantitative, mechanistic, dose-response model of the cellular pathway that is perturbed by 

perchlorate, and then the subsequent use of pharmacokinetic modeling to identify a human 

perchlorate exposure level that prevents the perchlorate from reaching a toxic concentration at 

the NIS. Therefore, the OIG used the Tonacchera Model to conduct a cumulative risk 

assessment of this public health issue. 

2.5 EPA Risk Assessment Procedures 

2.5.1 EPA Risk Assessment Guidance 

EPA risk assessment guidance provides procedures for combining the risk from multiple 

chemicals (i.e., a chemical mixture) sharing the same “mode of action.” These risk assessment 

procedures are identified in the following EPA risk assessment guidance documents: the 1986 

Guidelines for the Health Risk Assessment of Chemical Mixtures (EPA/630/R-98/002) and the 

2000 Supplementary Guidance for Conducting Health Risk Assessment of Chemical Mixtures 

(EPA/630/R-00/002). EPA assumes the toxicity of individual chemicals in a chemical mixture 

add together (i.e., dose additivity) when the chemicals have the same mode of action and elicit 

the same effects. EPA’s risk assessment guidance identifies the use of a dose-addition method 

for combining risk from components of a chemical mixture (e.g., multiple agents or stressors). 

EPA defines a chemical mixture as the concurrent or sequential exposure of two or more 

chemicals regardless of source, timing, or location of exposure (i.e., the chemicals do not have to 

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physically exist as a mixture outside the body or be consumed as a mixture to be a chemical 

mixture for environmental risk assessment purposes). 

EPA’s own risk assessment guidance instructs the agency to aggregate the risk from 

multiple chemicals or stressors sharing the same mode of action. The following sections of 

EPA’s risk assessment guidance provide details on the dose-addition model for combining risk 

from multiple chemicals having the same mode of action using relative potency factors: 

•	 The 1986 EPA Guidelines for the Health Risk Assessment of Chemical Mixtures 

recommends three approaches for the quantitative health risk assessment of a 

chemical mixture (e.g., multiple agents or stressors) (EPA 1986; EPA 2000, section 

2.2.1). This guidance defines a chemical mixture as the concurrent or sequential 

exposure of two or more chemicals regardless of source, timing, or location of 

exposure (i.e., the chemicals do not have to physically exist as a mixture outside the 

body or be consumed as a mixture to be a chemical mixture for environmental risk 

assessment purposes) (EPA 1986, p 1). In section 4.1 of this 1986 EPA guidance 

document, the third recommended approach allows for a risk assessment of a 

chemical mixture by using a dose-addition model with potency adjustment if the 

chemicals act as dilutions or concentrations of each other (EPA 1986, p 16). 

•	 In 2000, EPA supplemented this chemical mixture guidance by publishing the 

Supplementary Guidance for Conducting Heath Risk Assessment of Chemical 

Mixtures (EPA 2000). Section 2.6.1 of this supplementary guidance provides details 

on using the dose-addition method for combining the risk from multiple of chemicals 

having the same mode of action (EPA 2000). 

2.5.1.1 Applying the Dose Addition Method 

Since 1986, the EPA risk assessment procedures have allowed the amount of NIS 

inhibition from thiocyanate, nitrate, perchlorate, and the lack of iodide to be combined through 

dose addition by the use of relative potency factors for the purposes of conducting a human risk 

assessment. The biochemical properties and mechanistic interaction of the four NIS stressors 

meet the following EPA risk assessment requirements for the use of the dose-addition method: 

•	 Same mechanism of toxicity (all four NIS stressors act on the NIS to limit the amount 

of iodide uptake by the thyroid) 

•	 Similar dose-response3

 curves (e.g., same slopes, different x-axis intercepts) 

•	 Act independently of one other; act as dilutions of one another 

•	 Known relative potency factors for each NIS stressor 

•	 Behave similarly in terms of the primary physiologic processes (i.e., uptake, 

metabolism, distribution, and elimination) 

•	 Human exposures of each chemical are known (including at various life stages) 

3 A dose-response is the relationship between a quantified exposure (dose) and the proportion of subjects 

demonstrating specific biologically significant changes in incidence and/or in degree of change (response). 

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Therefore, the OIG Analysis conducted a cumulative risk assessment of this public health issue 

using the dose-addition method. 

By contrast, an alternative approach to conducting a risk assessment is the whole mixture 

approach, which risk assessors can accomplish by developing a statistical model on human 

epidemiological data. An example of this approach that has received a lot of attention is the 

Blount analysis and the subsequent Steinmaus analysis of the National Health and Nutrition 

Examination Survey (NHANES) 2001-2002 epidemiological study. We address the whole 

mixture approach for conducting a cumulative risk assessment in Appendix A. 

2.5.2 EPA Development of Cumulative Risk Assessments 

In 1997, the EPA Administrator directed the Agency “to take into account cumulative 

risk issues in scoping and planning major risk assessments and to consider a broader scope that 

integrates multiple sources, effects, pathways, stressors, and populations for cumulative risk 

analysis in all cases for which relevant data are available” and to “embrace this cumulative 

approach” in all major risks assessments (EPA 1997b). In May 2003, EPA published 

Framework for Cumulative Risk Assessment (EPA/600/P-02/001F), which establishes a 

framework to develop guidance on conducting and evaluating cumulative risk assessments and to 

provide basic concepts and principles to be addressed in a cumulative risk assessment. The 

document’s primary purpose is to offer a simple, flexible structure for conducting and evaluating 

cumulative risk assessments within EPA. This framework is neither a procedural guide nor a 

regulatory requirement within EPA. EPA states it expects cumulative risk assessment to evolve 

with experience. The following section of the Framework for Cumulative Risk Assessment 

identifies that the risk from stressors with a common mode of action are assessed together and 

that the dose-addition method can be applied: 

•	 In section 3.2.2.1, the EPA Framework for Cumulative Risk Assessment identifies that 

for situations of toxicological similarity, “the stressors are grouped according to the 

common mode of action . . . during the planning and scoping phase [of the risk 

assessment].” “For all effects caused by that mode of action, dose addition can be 

applied to the stressor group.” 

In May 2007, EPA issued four white papers on how cumulative assessment differs from 

traditional assessment and how EPA could assess cumulative risk (Callahan 2007; deFur 2007; 

Sexton 2007; Ryan 2007). The application of cumulative risk assessment has the potential to 

expand our understanding of the public health impacts of environmental exposures (Fox 2004) 

and provides a clearer, more complete picture of a public health issue for making risk 

management decisions (EPA 2003, appendix A). Cumulative risk assessment will reduce risks 

to the extent that it can be integrated into prevention strategies to track and protect public health 

(Fox 2004). 

On June 27, 2008, EPA issued Concepts, Methods, and Data Sources for Cumulative 

Health Risk Assessment of Multiple Chemicals, Exposures, and Effects: A Resource Document 

(EPA/600/R-06/013F), which identifies specific elements of and approaches for implementing 

cumulative risk assessments. This document demonstrates the feasibility of including 

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combinations of chemicals, exposures, effects, and their interactions into a cumulative risk 

assessment, and is meant to assist with the conduct of multichemical, population-focused 

assessments. However, this resource document specifically identifies in its preface that it is 

neither a regulatory document nor guidance (EPA 2008, p xvii). Although EPA’s Office of 

Research and Development (ORD) has made progress in developing resource documents to 

conduct cumulative risk assessments, ORD has not developed Agency-wide guidance or 

regulations for conducting a cumulative risk assessment. 

By contrast, as required by Section 405 of the Food Quality Protection Act of 1996 [P.L. 

104-170], EPA’s Office of Pesticide Programs (OPP) issued on January 14, 2002, Guidance on 

Cumulative Risk Assessment of Pesticide Chemicals that Have a Common Mechanism of 

Toxicity. This cumulative risk assessment guidance applies to pesticides and begins by 

identifying a group of pesticides that induce a common toxic effect by a common mechanism of 

toxicity. OPP had conducted four cumulative risk assessments on the following classes of 

pesticides sharing the same mechanism of toxicity: n-methyl carbamate, organophosphate, 

triazine, and chloroacetanilide. 

2.6 Implementing a Cumulative Risk Assessment 

Our approach to conducting a cumulative risk assessment was to apply the NAS Toxicity 

Testing Committee’s strategy and vision to this public health issue. The in vitro modeling is 

required because as the complexity of the risk assessment increases (i.e., more factors evaluated), 

animal testing becomes neither practical nor sensitive enough to observe and define the 

relationship between an increasing number of stressors. For example, four stressors each 

administered at three different doses (i.e., high, medium, and low) would require 81 separate 

animal studies to evaluate the 34 possible combinations. To conduct 81 perchlorate animal 

studies is impractical. Furthermore, no scientific techniques are available to measure subtle 

cognitive deficits in rat offspring. 

We used TIU as the basis for the cumulative risk assessment because the NAS 

Committee identified the TIU as the key biochemical event and recommended the use of TIU as 

the basis for a perchlorate risk assessment. The TIU is the combined effect of all four NIS 

stressors acting on the thyroid. We identified the Tonacchera Model as a mathematical model 

that defines the relationship between the four NIS stressors (thiocyanate, nitrate, perchlorate, and 

lack of iodide) and the TIU by the NIS. Therefore, the Tonacchera Model combines the risk 

from multiple chemicals into a single variable, the TIU, which measures the cumulative effect on 

the thyroid to the simultaneous exposure to all four NIS stressors. Thus, the Tonacchera Model 

utilizes both the NAS Toxicity Testing Committee’s strategy and vision and EPA’s dose-addition 

method to conduct a cumulative risk assessment of this public health issue. 

The application of an in vitro model to assess environmental risk is unprecedented, but is 

required to address the complexity of multiple stressors affecting this public health issue. 

Instead of the conventional single chemical risk assessment approach of identifying an external 

dose that results in an adverse effect, our approach identified the maternal TIU that is associated 

with subtle mental deficits in a developing child. TIU is not an external dose of a single 

chemical, but the combined biological effect of all four NIS stressors acting on the thyroid. So 

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addressing this public health issue requires preventing the excessive exposure to any single NIS 

stressor to assure the maternal TIU does not reach a level that induces toxicity. 

Section 3.1.3 of EPA’s Draft Guidance on the Development, Evaluation, and Application 

of Regulatory Environmental Models (November 2003) establishes that all environmental models 

should be corroborated before they are used as the basis of rule-making or regulation. We have 

corroborated the Tonacchera Model against several available human exposure studies. The OIG 

Analysis found the calculated TIU to be both a good predictor of an adverse outcome and a good 

explanation for the observed toxicity of the NIS stressors. 

2.6.1 Aspects in Implementing a Cumulative Risk Assessment 

Cumulative risk is defined as “the combined risks from aggregate exposure to multiple 

agents or stressors” (EPA 2003, p 6). The 1992 Expert Panel on the Role of Science at EPA 

points out that EPA has historically focused on chemical-specific impacts (EPA 1992, p 14). In 

1994, NAS issued a recommendation to move away from single-chemical assessments (NAS 

1994, executive summary p 13; EPA 2000, p x (first bullet)). In 1997, former EPA 

Administrator Browner wrote, “For most of our history, EPA has assessed risks and made 

environmental protection decisions based on individual contaminants . . . . with risk assessments 

for these chemicals often focused on one source, pathway, or adverse affect” (EPA 1997b). 

Likewise, in 1997, the U.S. EPA Science Policy Council stated that EPA’s risk assessment 

should evolve away from a focus on the potential adverse effect of a single pollutant in one 

environmental medium (Callahan 2007). Unfortunately, both EPA’s 2002 draft perchlorate risk 

characterization (EPA 2002a) and the NAS Committee on perchlorate (NAS 2005) focused 

solely on perchlorate and did not include in their assessments the quantitative impact of the other 

stressors that are known to affect the uptake of iodide by the thyroid. For this public health 

issue, perchlorate is not the only stressor that inhibits the uptake of iodide by the NIS. 

Thiocyanate and nitrate are also NIS inhibitors and human exposure to them is common, from 

both natural and manmade sources, and is unavoidable in the diet. A cumulative risk assessment 

of this public health issue must incorporate the inhibition from all three NIS inhibitors to produce 

a broader, more comprehensive understanding and assessment of the factors involved that lead to 

the unacceptable adverse effect of permanent, subtle mental deficits in children. 

Another critical aspect of a cumulative risk assessment is that a stressor does not have to 

be the exposure to a chemical, but the “absence of a necessity” (EPA 2003, p 2). This concept is 

critical to this public health issue; the NIS uptakes iodide from the blood in order to make the 

iodide-containing thyroid hormones T3 and T4. An adequate supply of iodide in the human diet 

is essential for the production of iodide-containing thyroid hormones and their subsequent supply 

to the body. If the human diet lacks a sufficient supply of iodide, at specific level of iodide 

deficiency for a given NIS inhibitor load, the thyroid becomes unable to meet the body’s 

minimum requirement for thyroid hormones. Therefore, the lack of iodide in the diet (i.e., the 

absence of a necessity) is also a stressor for this public health issue. Subsequent analysis will 

show the lack of iodide to be the dominant stressor in this public health issue. The iodide 

nutritional level must be quantitatively factored into the human health risk assessment. 

Unfortunately, both EPA’s 2002 draft perchlorate risk characterization (EPA 2002a) and the 

NAS Committee on perchlorate (NAS 2005) did not quantitatively factor in iodide nutrition into 

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their reviews. By contrast, cumulative risk assessment allows for the lack of this necessity to be 

quantitatively factored into the human health risk assessment in order to fully characterize this 

public health issue. The relative contribution of the lack of iodide stressor on the uptake of 

iodide by the NIS is quantitatively defined in the Tonacchera Model (Tonacchera 2004). 

Furthermore, since the lack of iodide can be shown to be the dominate stressor effecting this 

public health issue, it is essential that the lack of iodide be quantitatively included in the human 

risk assessment. 

The fundamental task in a cumulative risk assessment is to combine the toxicity of 

individual chemicals that share the same toxicity pathway. The toxicity of the individual 

chemicals sharing the same toxicity pathway can be combined additively by using relative 

potency factors (Callahan 2007; Sexton 2007). Since 1986, EPA guidance has allowed the 

amount of NIS inhibition from thiocyanate, nitrate, and perchlorate to be combined through dose 

addition by the use of relative potency factors for the purposes of conducting a human risk 

assessment. Under section 2.6.1 of the EPA Supplementary Guidance for Conducting Heath 

Risk Assessment of Chemical Mixtures, for chemicals having the same mode of action, similar 

dose-response curves, if the chemicals act as dilutions of each other and behave similarly in 

terms of the primary physiologic processes (i.e., uptake, metabolism, distribution, and 

elimination), and the exposures of each chemical are known, then the procedure suggested for 

estimating risk uses relative potency factors (EPA 2000, p 28-29). The relative potency factors 

approach scales the relative toxicity of each chemical (i.e., stressor) to the potency of an index 

chemical (i.e., typically the best-studied component of the mixture) (EPA 2000, p 29). 

Both EPA’s 2002 draft perchlorate risk characterization (EPA 2002a) and the NAS 

Committee on perchlorate (NAS 2005) did not utilize the dose-addition approach to human risk 

assessment, and did not quantitatively incorporate the other NIS inhibitors into their reviews. In 

EPA’s perchlorate briefing to the NAS Committee on October 27, 2003, EPA stated that the 

Agency recognizes the “potential cumulative burden of toxicity” of the other NIS inhibitors, but 

describes comparisons of perchlorate toxicity to the other NIS inhibitors as “nonproductive” 

(Farland 2003). EPA is referring to the scientific community’s comparison of perchlorate 

toxicity to the other NIS inhibitors: thiocyanate and nitrate. For example, an article in the 

European Journal of Endocrinology indicates that the daily perchlorate equivalent concentration 

(PEC) intake from the ingestion of thiocyanate and nitrate in the U.S. Department of Agriculture 

(USDA) recommended diet is 670 times higher than the amount allowed for by the perchlorate 

RfD (De Groef 2006). This paper also indicates that the concentration of nitrate allowed in 

drinking water would cause an amount of NIS inhibition that is 12 times greater than the 

perchlorate RfD. Likewise, Intertox, Inc. also compares the amount of inhibition from 

thiocyanate and nitrate in the USDA recommended diet against the perchlorate RfD (Bruce 2003, 

Bruce 2005). The OIG agrees with EPA that comparing perchlorate toxicity to the other NIS 

inhibitors individually is not a constructive approach to assessing or addressing this public health 

issue. We have this opinion because the human body is exposed to all three NIS inhibitors 

concurrently and the resulting effect of each on the uptake of iodide by the thyroid is cumulative 

and indistinguishable from the others, the perchlorate risk characterization must include exposure 

to all three NIS inhibitors. The perchlorate risk characterization performed by EPA and NAS is 

incomplete because the exposure from only a single NIS inhibitor was evaluated. The risk from 

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the cumulative inhibition effect of all three NIS inhibitors is best assessed through a cumulative 

risk assessment. 

Another critical aspect of a cumulative risk assessment is to incorporate the risk from the 

background exposure to the stressors because the exclusion of a stressor(s) or the background 

exposure from a stressor(s) “may seriously distort” the portion of the total estimated risk 

attributed to the principal stressor of concern (EPA 2003, appendix C). Cumulative risk 

assessment distinguishes between background exposures and source specific exposures to 

provide a more complete picture of both total and source-related risks (EPA 2003, appendix C). 

For a perchlorate cumulative risk assessment, the background exposure levels and sources of 

each of the four stressors need to be determined and clearly distinguished from a specific source 

exposure. The Tonacchera Model identifies the lack of iodide in the diet as the dominant 

stressor. When the contribution of iodide is not quantitatively factored in to the risk assessment 

(i.e., as in a single chemical assessment done for perchlorate), the result is seriously distorted. 

Likewise, when the contribution of the other NIS inhibitors is not quantitatively factored in the 

perchlorate risk assessment, the result is seriously distorted. When concurrent exposure to all 

three NIS inhibitors is considered, perchlorate’s contribution to the body’s total inhibitor load is 

only a small portion of the body’s total inhibition load. Knowing the various sources and the 

amount of contribution of each of the NIS inhibitors to the body’s total inhibition load provides a 

clearer, more complete picture of this public health issue for making risk management decisions. 

EPA’s Framework for Cumulative Risk Assessment stated, “For most exposure situations, 

hazard and dose response studies of all of the joint effects from the multiple stressors will not be 

available, so that conclusions will have to be based at least partly on the single stressor 

information.” For perchlorate, a risk characterization cannot be done in humans because adverse 

health effects have not been clearly demonstrated in any human population exposed to 

perchlorate. However, the Framework for Cumulative Risk Assessment identifies that the risk 

characterization of a cumulative risk assessment can be based on the adverse effects observed in 

one of the stressors and subsequently applied to the joint effects from all of the multiple 

stressors. Therefore, the risk characterization of the four NIS stressors should be done by using a 

NIS stressor in which adverse effects in children born to mothers with low maternal TIU during 

pregnancy and nursing have been documented and reported. The excessive maternal exposure to 

the NIS stressor, the lack of iodide, is the principal NIS stressor in which adverse effects have 

been documented and reported in children born to mothers with low maternal TIU during 

pregnancy and nursing. Thus, the OIG Analysis characterized the adverse effects from the lack 

of iodide stressor and used this information to conduct the initial three steps in a risk 

characterization (i.e., hazard characterization, dose-response assessment, and exposure 

assessment) of this public health issue. The exposure to the lack of iodide stressor was related 

back to the joint exposure level of all four NIS stressors by integrating the joint exposure into a 

single parameter or “common metric.” The single parameter for measuring the NIS stress level 

is the TIU. The Tonacchera Model approach was to mathematically calculate the resulting TIU 

level from the concurrent joint exposure to all four NIS stressors. 

The cumulative risk assessment “also includes aspects of cumulative risk that may be 

outside of EPA’s current legislative mandates and where expertise outside of the Agency would 

be needed to address certain questions if they should arise” (EPA 2003, p xviii). EPA authority 

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extends to the regulation of environmental contaminates. However, according to the Tonacchera 

Model, the dominant stressor in this public health issue is the iodide nutrition level (i.e., the lack 

of iodide in the diet). Overseeing the iodide nutrition level is clearly not in EPA’s legislative 

mandate, but addressing the needs of iodide-deficient pregnant women in the U.S. population is 

necessary to effectively address this public health issue. The NAS Committee was qualitatively 

aware of the crucial role of an adequate supply of iodide during pregnancy, so much so that the 

NAS Committee “ . . . recommends that consideration be given to adding iodide to all prenatal 

vitamins” (NAS 2005, p 18). However, under the 1994 Dietary Supplement Health and 

Education Act, the FDA does not approve dietary supplements or have the legislative mandate to 

evaluate whether prenatal vitamins should contain iodide (FDA 2007b). Under the Act, the 

dietary supplement manufacturers are responsible for determining supplement’s safety and the 

selection of ingredients for a dietary supplement (i.e., if iodide is to be added to prenatal 

vitamins). The medical community, not EPA, is responsible for any practice to identify and treat 

iodide deficiency in pregnant women with iodide containing prenatal vitamins or other 

treatment(s). Therefore, EPA’s potential regulation of perchlorate exposure from the 

environment represents only a small portion of both the problem and solution to this public 

health issue. Furthermore, addressing this public health issue will require a diverse group of 

agencies, organizations, and disciplines to fully characterize and address the issue. 

Another key aspect is that cumulative risk assessments can be qualitative as well as 

quantitative (EPA 2003, p 7 and section 3.3.4, p 58). This aspect is important because it allows 

for the incorporation of risk from other chemical exposures in which there is insufficient 

information to quantify accurately the risk, but scientists know the presence and nature of the 

risk. With respect to this public health issue, the uptake of iodide is not the only step in the 

production and use of thyroid hormones in the body that is disrupted by chemical exposures. 

Numerous inorganic and synthetic chemicals have been documented to interfere with almost 

every major step in the production, transport, and peripheral tissue metabolism of thyroid 

hormones (Howdeshell 2002, p 344, table 1). Furthermore, perchlorate, thiocyanate, and nitrate 

are not the only chemicals that disrupt the uptake of iodide by the thyroid. The following table 

provides examples of chemicals that interfere with several major thyroid hormone steps: 

Thyroid Hormone Step Examples of Chemicals that Interfere 

Iodide uptake by the NIS 2,4-D, Aldrin, Lead, PBBs, 

Iodide oxidation by thyroid peroxidase Lindane, Malathion, Mancozeb 

Circulatory transport in blood 

(e.g., binding to transthyretin) 

Dioxtylphthalate, DDT metabolites, 

Dichloroprop, Difocol, Lindane, Malathion, 

Cellular metabolism of T4 to T3 by Type I or Type II 5’­

deiodinase in peripheral tissues Cadmium, Lead, PCB, Dixoin 

Increase cellular elimination by glucuronidation of T4/T3 by 

the stimulation of the glucuronidase enzyme Acetochlor, DDT, PBBs, PCBs, Dioxin 

Source: Howdeshell 2002 (for full list, see p 344, table 1). 

Therefore, any risk assessment and resulting risk management decision(s) addressing this 

public health issue must also incorporate the nonquantified risk from the exposure to other 

thyroid hormone disrupting chemicals in order to be fully effective and protective of human 

health. Section 3.3.4 of EPA’s Framework for Cumulative Risk Assessment introduces 

qualitative approaches to risk assessment (EPA 2003). Qualitative approaches may be the only 

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practical means to overcome the problems of complexity and data deficiencies and provide some 

insight into the nature and magnitude of cumulative risks (Callahan 2007). 

In conclusion, the nature of this public health issue not only meets the requirements to be 

addressed by a cumulative risk assessment approach, but the complexity of the interaction among 

three NIS inhibitors and the iodide nutritional level requires the use of a cumulative risk 

assessment approach to accurately characterize the nature of the problem and to identify 

effective and cost-efficient solutions to the problem. Presidential Executive Order 12898, the 

intent of Congress under the Food Quality Protection Act of 1996, the 1997 direction given by 

former EPA Administrator Browner, and EPA’s own risk assessment guidance directs EPA to 

consider cumulative risk analyses in all cases for which relevant data are available. The 

documented interaction of the three NIS inhibitors – thiocyanate, nitrate, and perchlorate – and 

the role of iodide nutrition in the uptake of iodide meet EPA’s criteria for using cumulative risk 

assessment to address this public health issue. The three NIS inhibitors exceed EPA’s mode of 

action requirement by sharing the same mechanism of toxicity (i.e., simple competitive 

interaction) by inhibiting the uptake of iodide at the NIS. The term “mechanism of activity” is a 

more detailed understanding and description of the events at the molecular level meant by “mode 

of action” (EPA 2000, p 10). As also required by EPA guidance for dose addition, the doseresponse curves of thiocyanate, nitrate, and perchlorate have the exact same shape (Tonacchera 

2004, figure 1). As also required by EPA guidance for dose addition, the three anions act as 

concentrations or dilutions of each other (Tonacchera 2004). The relative potency factors for 

each of the three NIS inhibitors are known (Tonacchera 2004). Human exposure data are 

available on each of the four stressors (i.e., the three NIS inhibitors and iodide nutrition). Since 

the EPA requirements for using the dose-addition method are met, there are no significant 

technical reasons not to use cumulative risk assessment to characterize the risk to the public. 

The only serious technical difficulty in implementing cumulative risk assessment is lack of 

experience and familiarity with cumulative risk assessment in the risk assessor community. 

2.7 Summary of the OIG Approach 

In the opinion of the OIG, the complexity of this public health issue requires the use of a 

cumulative risk assessment approach to better understand and characterize all the factors 

contributing to this public health issue and to identify an effective and cost-efficient solution to 

this problem. Based on the review of the EPA risk assessment guidance, the OIG could simply 

just recommend the Agency conduct a cumulative risk assessment on perchlorate. However, due 

to the novelty of the cumulative risk assessment approach and the required judgment in applying 

the science in a cumulative risk assessment, the OIG has undertaken the unusual step of 

providing an example of how a cumulative risk assessment could be conducted on perchlorate. 

This example will demonstrate the advantages of using the cumulative risk assessment approach 

and provide insight into potential cost-effective remedies to this public health issue. The use of 

an in vitro model to evaluate potential remedies of a public health issue is not unfounded; the 

NAS Toxicity Testing Committee stated, “In some risk contexts, a dose-response model based 

on in vitro results might provide adequate data to support a risk-management decision” (NAS 

2007). The application of a cumulative risk assessment approach using the Tonacchera Model 

will allow the OIG to make recommendations on needed scientific research, comment on the 

28
 
10-P-0101 

current regulatory approach to address the issue, and identify potential cost-effective remedies 

for consideration. 

29
 
 

10-P-0101 

3. Sodium (Na+)/Iodide Symporter (NIS) Inhibitors 

3.1 Background 

Sufficient exposure to perchlorate can cause human toxicity by competitively inhibiting 

transport of iodide into the thyroid gland by NIS (NAS 2005, p 6). The NAS Committee 

identified the inhibition of iodide uptake by the thyroid in humans as the key biochemical event. 

The NAS Committee recommended using the inhibition of NIS as the point of departure (POD) 

for human risk assessment. The NAS Committee describes NIS inhibition as a nonadverse effect 

that precedes all adverse effects from perchlorate exposure. The NAS Committee-recommended 

RfD of 0.0007 mg/kg-day was established from a perchlorate exposure level that did not cause a 

decreased uptake of iodide in adults. 

Since the NAS Committee recommended using NIS inhibition as the POD for human risk 

assessment and used the NIS inhibition to establish a perchlorate RfD, a full understanding and a 

working quantitative model of this key biochemical event is critical to effectively protect human 

health from the adverse effects from perchlorate exposure. The NIS is a trans-phospholipid 

membrane protein that actively transports both sodium and iodide ions (i.e., an ion pump) across 

the cell’s plasmid membrane from the blood serum into the thyroid’s follicular cells. The ion 

transport is in the same direction. The concentration of iodide ion from the blood serum into the 

thyroid’s follicular cells is energetically unfavorable. Therefore, the energy from the cotransport of two sodium ions down sodium’s electrochemical gradient allows an iodide ion to 

move against its electrochemical gradient and into the cell (Carrasco 2005). 

Although NIS has a high affinity for the iodide ion, NIS is also known to transport a wide 

variety of monovalent anions with a similar ionic radii to iodide (De Groef 2006; Carrasco 

2005). The following monovalent anions are known to be able to concentrate in the thyroid or to 

inhibit the NIS: pertechnetate (TcO4

-

), perchlorate (ClO4

-

), perrhenate (ReO4

-

), thiocyanate 

(SCN-), boron tetrafluoride (BF4

-

), iodide (I-), nitrate (NO3

-

), bromide (Br-), chloride (Cl-), 

chlorate (ClO3

-

), selenocyanate (SeCN-), periodate (IO4

-

), and bromate (BrO3

-

) (Carrasco 2005; 

Wolff 1998; Dohan 2007). The relative NIS potencies of some of these anions are as follows 

(Wolff 1998): 

TcO4- ≥ ClO4

- > Re04- > SCN- > BF4- > I- > NO3- > Br- > ClNotice that the iodide anion does not have the highest affinity for the NIS. Furthermore, both 

perchlorate and thiocyanate have a higher affinity for NIS than iodide. 

3.2 Relative Potencies of Other NIS Inhibitors 

Humans are exposed nutritionally and environmentally to other NIS inhibitors, in 

addition to perchlorate, which also competitively inhibit the uptake of iodide. The other 

principal NIS inhibitors of concern of human exposure are thiocyanate (SCN-

) and nitrate 

(NO3-

). As far back as 1953 (Wyngaarden 1953), the relative NIS inhibition potencies of 

prevalent nutritional and environmental NIS inhibitors (i.e., perchlorate, thiocyanate, and nitrate 

30
 
 

10-P-0101 

perchlorate) have been studied and quantifed repeatedly with excellent agreement in the results. 

The following table provides a summary of these NIS inhibitor potency studies and their results: 

Study Study Description 

Relative Potency* of NIS Inhibitor 

Perchlorate Thiocyanate Nitrate 

Tonacchera 2004 

In vivo CHO** cells expressing the 

human NIS 1 15 240 

Alexander 1966 

In vivo 50% thyroid weight 

increase in rats 1 20 550 

Alexander 1966 In vitro rat thyroid slices 1 20 400 

Greer 1966 In vitro rat thyroids 1 20 240 

Wyngaarden 1953 In vivo rat 1 10 300 

* Relative Potency is based on molar concentrations of each anion. 

** Chinese hamster ovary
 

Source: De Groef 2005. 

3.3 Human Thiocyanate Exposure 

Vegetables are a significant and natural source of thiocyanates (Tonacchera 2004). At 

least 2,500 taxa in the plant kingdom contain cyanogenic glycosides (CGs) (Vetter 2000). Plants 

use the CGs as a source to generate hydrogen cyanide, which serves as a feeding deterrent to 

grazing animals or insects. Upon human ingestion, the CG-containing plants release cyanide. 

The sulfurtransferase enzyme, rhodanese, metabolizes and detoxifies the released cyanide into 

thiocyanate (WHO 2004; Hasuike 2004). Therefore, the natural act of eating routinely exposes 

humans to the relatively potent NIS inhibitor thiocyanate. As a result, the human body always 

has a certain amount of unavoidable exposure to NIS inhibitors and this is referred to as the 

body’s goitrogen load. 

Foods particularly rich in thiocyanate include cabbage, broccoli, Brussels sprouts, corn 

(maize), turnips, rapeseed, and mustard seed. Furthermore, cauliflower, cabbage, radishes, 

spinach, and tomatoes contain on average 88, 86, 7, 5, and 2 mg/kg (wet weight) of thiocyanate, 

respectively. Milk contains 2-10 mg/L thiocyanate. In some parts of the world, the consumption 

of cassava is the major source of thiocyanate. Cassava can contain the equivalent of up to 3,400 

mg/kg of thiocyanate (dry weight). Where cassava is not a significant part of the diet, cyanide 

produced and absorbed by cigarette smoking is the most significant source of thiocyanate. 

Thiocyanate serum concentration in nonsmokers is typically in the range of 10-70 

μmol/L. By contrast, the thiocyanate serum concentration of smokers is higher, typically in the 

range of 80-120 μmol/L. 

Thiocyanate may have a regulatory function in normal physiology (Middlesworth 1986). 

Thiocyanate is continuously synthesized in the normal rat. In the absence of all dietary intake of 

thiocyanate in the rat, the thiocyanate serum concentration actually increased from 500 μg/dl to 

800 μg/dl during fasting (Middlesworth 1986, figure 1). These data indicate that serum 

thiocyanate in rats is maintained in a normal range. These data also imply that humans also 

synthesize and maintain thiocyanate serum concentrations in a normal range. A “kidney 

threshold” is reported to exist in humans at a thiocyanate serum threshold of 200-300 μmol/L 

(Tonnacchera 2004). 

31
 
 

 

 

10-P-0101 

By comparison, the EPA perchlorate RfD of 0.0007 mg/kg-day results in a perchlorate 

serum concentration of 0.014 μmol/L. By contrast, the daily thiocyanate exposure in 

nonsmokers results in a thiocyanate serum concentration in the range of 10-70 μmol/L. 

Therefore, thiocyanate exposure is a significant component of the body’s goitrogen load. 

3.4 Human Nitrate Exposure 

Nitrate is also common in food (Tonacchera 2004). Nitrate occurs in green leafy 

vegetables. The consumption of vegetables is the primary source of nitrate exposure (NAS 1995, 

p 35). In 1981, the National Research Council (NRC) estimated that 97% of the daily nitrate 

intake is from diet (99% for vegetarians) (NAS 1995, p 40, table 4-2). However, nitrate is also 

added to processed meats as a preservative. Furthermore, both surface and ground sources of 

drinking water commonly contain nitrate due to the agricultural use of inorganic fertilizers, 

animal manure, and airborne emissions from utilities, factories, and automobiles. In areas of 

intensive agriculture, fertilizer usually is the predominant source of nitrogen. Animal manure 

and atmospheric deposition account for smaller amounts of nitrogen contributions nationally 

than commercial fertilizer, but are significant secondary sources of nitrogen in certain regions. 

In vegetables, the highest nitrate concentrations are found in celery, spinach, lettuce, 

beets, radishes, melon, turnip greens, and rhubarb (over 1000 mg/kg of vegetable), (NAS 1995, 

p 35). Dairy products contain low concentrations of nitrate and rarely exceed 5 mg/kg in milk 

(NAS 1995, p 36). The following table provides a list of common foods that contain nitrate: 

Common Foods Containing Nitrates 

Milk Kimchi Carrots 

Bacon Garlic Onion 

Sausage Artichoke Green beans 

Pepperoni Peas Melon 

Beef Corn Turnip 

Ham Sweet potatoes Sweet pepper 

Broccoli Lima beans Squash 

Celery Cucumber Cabbage 

Lettuce Tomatoes Leek 

Radish Parsley Cauliflower 

Spinach Brussels sprouts Pumpkin 

Beets White potatoes Endive 

Rhubarb Eggplant Kale 

Turnip greens 

Source: Bruce 2004. 

Human exposure to nitrate is both exogenous and endogenous. Exogenous human nitrate 

exposure is from diet through the consumption of primarily vegetables. The endogenous human 

nitrate exposure is from the body’s production of nitric oxide, which is subsequently converted 

into nitrate by various types of cells in the body (NAS 1995, p 37). Therefore, nitrate excretion 

in urine exceeds the nitrate intake from food and water. Thus, biomonitoring of nitrate in human 

urine cannot be directly used to assess exogenous nitrate exposure. 

32
 
10-P-0101 

The amount of human nitrate exposure has been assessed and estimated several times. In 

1981, the NRC estimated nitrate intake from food at 40-100 mg/day for males (NAS 1995, p 38) 

and that nitrate intake from contaminated water could contribute 22-44 mg/L (NAS 1995, p 38). 

In 1998, European investigators report an average dietary nitrate intake of 43-131 mg/day (NAS 

1995, p 39). In 1989, Van den Brandt estimated the exogenous nitrate intake at 113 mg/day for 

males and 184 mg/day for females (NAS 1995, p 38). In 1992, Jones estimated exogenous 

nitrate intake in the United States for omnivores at 76 mg/day and about 260 mg/day for 

vegetarians (NAS 1995, p 38). Jones estimated the endogenous production of nitrate to be 62 

mg/day (NAS 1995, p 38), which contributes about 45% of a human’s total nitrate exposure 

(NAS 1995, p 38). Jones estimated the total exogenous and endogenous nitrate exposure to be 

138 mg/day (NAS 1995, p 38). 

In studies from Denmark and the United Kingdom, the average daily nitrate intake is 

estimated to be about 40-50 mg/day for adults (Tonacchera 2004). This nitrate intake value of 

40-50 mg/day is on the low end of the nitrate intake estimates reported above. Fortunately, these 

data also include the corresponding internal nitrate serum concentrations, which allows for the 

subsequent calculation of both the amount of NIS inhibition acting on the thyroid from nitrate 

exposure and the relative TIU by the thyroid under various NIS stressor levels. In the Western 

world, the typical nitrate serum concentration ranges from 10-140 μmol/L with the mean nitrate 

serum concentration being between 30-50 μmol/L (Tonacchera 2004). The serum half-life of 

nitrate is 5-8 hours (Tonacchera 2004). 

By comparison, the EPA RfD for perchlorate is 0.0007 mg/kg-day, which corresponds to 

a daily perchlorate exposure limit of 0.049 mg/day for a 70-kg adult. The daily nitrate intake of 

40-50 mg is substantially more (i.e., 1000 times greater on a weight basis) than both the daily 

perchlorate exposure limit calculated from the EPA RfD of 0.049 mg/day for a 70 kg adult and 

the .0046 mg/day median U.S. exposure to perchlorate estimated by the Centers for Disease 

Control and Prevention (CDC) biomonitoring data (Blount 2006). Therefore, nitrate exposure is 

also a significant component of the human body’s goitrogen load. 

3.5 Human Perchlorate Exposure 

The U.S. population is ubiquitously exposed to low levels of perchlorate. In 2006, 

Blount of the CDC, National Center for Environmental Health (NCEH), assessed the perchlorate 

exposure in the U.S. population using urinary biomonitoring data (Blount 2006a). As part of the 

2001-2002 NHANES, a nationally representative population of 2,820 U.S. residents (ages 6 

years and older) provided urine samples for perchlorate testing. All 2,820 urine samples tested 

found a detectable level of perchlorate (i.e., >0.05μg/L), indicating that perchlorate exposure in 

the U.S. population is common. The Blount biomonitoring data indicated median adult 

perchlorate exposure was 4.6 μg/day, and the 95th percentile exposure was calculated to be 16.4 

μg/day in an adult. Furthermore, the FDA TDS estimated lower- and upper-bound average 

perchlorate intakes (i.e., range of dietary perchlorate intake) for 2005-2006 from 5.4 to 6.8 

μg/day from food in 25- to 30-year-old women (Murray 2008, table 5). Therefore, both the CDC 

biomonitoring and the FDA TDS datasets indicate a low-level background exposure to 

perchlorate across the entire U.S. population. 

33
 
10-P-0101 

Potential sources of perchlorate exposure are through the Department of Defense/aerospace 

sector (e.g., rocket propellant), commercial products (i.e., safety flares and some fireworks (up to 

70% content)), agricultural use (i.e., perchlorate is a contaminant in CNF), and natural 

atmospheric production (Dasgupta 2006). The Department of Defense/aerospace sector use 

accounts for about 90% of the U.S. annual consumption of perchlorate (Dasgupta 2006). 

However, the burning of rocket propellants, safety flares, and perchlorate-containing fireworks 

does not result in a significant perchlorate exposure; 0.05% or less of the original perchlorate is 

left after use because the fire destroys the perchlorate (Dasgupta 2006). By contrast, the 

improper disposal of unused rocket propellants, safety flares, and perchlorate-containing 

fireworks, which allows the unused perchlorate to get into the groundwater and surface water, 

can result in human perchlorate exposure upon ingestion of contaminated drinking water. 

Although this type of improper disposal into water sources would generate “hot spots” of 

perchlorate exposure within the population, the improper disposal into water sources would not 

generate a uniform background of perchlorate exposure across the entire U.S. population, 

because EPA data indicate only 3.16% of the 3,858 Public Water Systems tested in the 

Unregulated Contaminant Monitoring Rule (UCMR) had at least one detection of perchlorate 

greater than or equal to 5 μg/L (EPA 2007, table 5). Natural production of perchlorate by the 

oxidation of chloride by lightning or ozone is not a significant source of drinking water 

contamination because rainfall contains a mean concentration of perchlorate of 0.015 μg/L (max. 

0.2 μg/L) (Dasgupta 2006). 

A potential route of perchlorate exposure that is consistent with generating a uniform low 

background exposure level in the entire U.S. population is the contamination of the U.S. food 

supply with perchlorate. The FDA TDS identifies that vegetables and dairy foods combined 

account for between 46% and 59% of the total estimated intake of perchlorate by teenagers and 

adults, respectively (Murray 2008). A potential explanation for the widespread perchlorate 

contamination of vegetables and dairy foods is the agricultural use of perchlorate-contaminated 

CNF from 1909 to at least 1993. Over the life of CNF use in the United States, the average 

perchlorate content of CNF is estimated to be 0.2% (Dasgupta 2006). The agricultural use of 

CNF is estimated to have resulted in the environmental release of 1.6 million pounds of 

perchlorate per year into U.S. agricultural fields for at least a 63-year period from 1930 to 1993 

(Dasgupta 2006). In short, there are few ways to introduce a chemical into the food chain that 

are more efficient than using fertilizer as a vector (Dasgupta 2006). 

34
 
 

 

10-P-0101 

4. Modeling the NIS Stressors’ Influence on the Total Iodide Uptake 

4.1 Determining the Total NIS Inhibition Load Acting on the Human Body

 The total NIS inhibition load (total goitrogen load) acting on the human body is the 

combined effect of all four common NIS inhibitors (i.e., thiocyanate, nitrate, perchlorate, and 

iodide). The Tonacchera study investigated the joint effects on the NIS from simultaneous in 

vitro exposure to these four NIS inhibitors (Tonacchera 2004). This study identified the 

interaction between the NIS inhibitors as being simple competitive interaction and observed no 

evidence of synergism or antagonism among the NIS inhibitors. These data indicate that these 

NIS inhibitors interact in a simple additive fashion. In other words, the in vitro effect on the NIS 

for each NIS inhibitor was indistinguishable from that of the others once adjusted for differences 

in concentration and potencies. Therefore, the total amount of in vitro NIS inhibition acting on 

the NIS is the combined contribution of each anion on a molar potency adjusted basis (i.e., the 

dose-addition method). Thus, the total inhibition acting on the NIS can be expressed as single 

PEC representing the same amount of NIS inhibition induced by the joint effect of all four NIS 

inhibitors. 

 The total amount of NIS inhibition (total goitrogen load) acting on the NIS in vitro is 

measured as a PEC and is defined in the Tonacchera study by the following equation: 

PEC = (Amt of ClO4

-

 Inhibition) + (Amt of NO3

-

 Inhibition) + (Amt of SCN- Inhibition) + (Amt of I- Inhibition) 

PEC = [ClO4

-

] + [SCN-] / 15 + [NO3

-

] / 240 + [I-] / 30 

However, the PEC equation needs to be adjusted into two mathematical forms to 

represent in vivo conditions when the amount of total NIS inhibition is being measured in the 

blood serum (i.e., serum perchlorate equivalent concentration (SPEC)) or measured from the 

weight of ingested NIS inhibitors consumed in the diet or through contaminated drinking water 

(i.e., oral perchlorate equivalent concentration (OPEC)). 

4.2 Serum Perchlorate Equivalent Concentration (SPEC) 

The body’s total NIS inhibition is measured by the following SPEC equation (concept 

adapted* from Tonacchera 2004): 

SPEC = (Amt of ClO4

-

 Inhibition) + (Amt of NO3

-

 Inhibition) + (Amt of free SCN- Inhibition) 

SPEC = [Perchlorate] + [Nitrate] /240 + ([total serum SCN-

] x 0.5) /15 

SPEC = [Perchlorate] + [Nitrate] /240 + [free SCN-

] /15 

Where: [ ] is molarity
 

Serum inhibition potency of perchlorate = 1 

Serum inhibition potency of nitrate relative to perchlorate = 1 / 240 

Serum inhibition potency of free thiocyanate relative to perchlorate = 1 / 15 

[free SCN- ]* = [total serum SCN-

] x 0.5 [free SCN- /total serum SCN-] 

35
 
 

10-P-0101 

* Note: Tonacchera’s PEC equation is derived from in vitro results and had to be 

adjusted to reflect in vivo conditions for the binding of thiocyanate to albumin in 

the blood stream (see discussion below). 

The SPEC equation relates the total NIS inhibition to the molarity of the each of the NIS 

inhibitors in the blood serum (i.e., the concentration of each NIS inhibitor in contact with the 

NIS protein). However, about half the thiocyanate in blood is bound to albumin (Stoa 1957). 

Therefore, only about half of the thiocyanate in human blood serum is free to interact and to 

inhibit the NIS protein on the thyroid. The experimental protocol used in Tonacchera’s study 

(from which each of the anion’s potency was determined) incubated the CHO cells expressing 

human NIS in Hank’s balanced salt solution, which contains 0.5% bovine serum albumin 

(Tonacchera 2004). By contrast, human plasma contains 4.8% albumin, by weight (Marieb 

1998). This textbook amount of albumin in blood plasma is consistent with the 4.4% and 4.6% 

found from direct measurements in nonsmoking and smoking controls, respectively (Hasuike 

2004, table 1). Therefore, the in vitro conditions in Tonacchera’s experimental protocol had only 

about 1/10th the amount of albumin found in blood plasma. 

The SPEC equation defined in this document is adapted from Tonacchera’s PEC equation 

by taking into account the in vivo conditions of having about 48 g/L of albumin in human blood 

serum that affect the amount of free thiocyanate. In five human test subjects having a total SCNserum concentration ranging from 1.96 mg/L to 2.55 mg/L (i.e., the range is equivalent from 

33.7 μmol/L to 43.9 μmol/L, which is in the typical SCN- range identified by Tonacchera), 47.2 

± 3.4 % of thiocyanate is bound to albumin (Stoa 1957, table 15). Or stated as free thiocyanate, 

52.8% of the total thiocyanate in the blood serum is free and unbound to albumin. In rabbit 

plasma at a higher SCN- concentration of about 141 & 280 μmol SCN-/L, 41.3% and 40.7% of 

thiocyanate is bound to the rabbit albumin, respectively (58.7 % and 59.3 % SCN-

 is free) 

(Pollay 1966, table 1). The amount of free SCN- increases with increasing SCN- concentration in 

the blood. Since SCN-

 in blood serum is typically 40 μmol/L, the amount of free SCN- from 

Stoa’s human data is used. Therefore, the amount of free SCN- at typical human SCNconcentrations can be determined by multiplying the total SCN- concentration by a factor of 

0.528. As the amount of SCN- increases, the amount of free SCN- also increases, but without 

having specific data for percent binding of SCN- to human albumin at different concentrations, 

the use of 0.5 in the SPEC equation represents a conservative estimate. Therefore, the 

thiocyanate term is adjusted by multiplying the total serum SCN-

 by 0.5 to derive the amount of 

available free thiocyanate in the blood able to interact and inhibit the NIS. 

Our analysis drops the amount of iodide inhibition term (i.e., [I-

]/30] in the original 

Tonacchera PEC equation in order to simply the mathematical expression for use in a cumulative 

risk assessment. Eliminating a minor term in a polynomial equation is standard mathematical 

technique used to simplify a problem. Eliminating the [I-

]/30 term in the PEC equation would 

not significantly alter the SPEC or OPEC-calculated values. The amount of NIS inhibition from 

iodide is a relatively small percentage of the OPEC value (i.e., about 0.1% of the OPEC of a 

typical adult exposure level). The typical adult consumes about 150 μg iodide/day. The oral 

inhibition potency of iodide is 1/30. So, a normal adult intake of 150 μg iodide/day represents 

the same amount of NIS inhibition as 5 μg of perchlorate (i.e., 1/10th the perchlorate RfD of 49 

μg/day). Since the perchlorate RfD has been calculated to represent about 1% of the body’s total 

36
 
 

10-P-0101 

goitrogen load, the iodide inhibition at 150 μg/day is about 0.1% of the body’s total goitrogen 

load. Furthermore, the lack of iodide is an NIS stressor, which acts in the opposite to its 

inhibition. As the iodide concentration decreases, resulting in more stress on the NIS, the 

amount of NIS inhibition from iodide becomes even less significant (i.e., a low intake of iodide 

at 50 μg/day causes the same amount of NIS inhibition as 1.7 μg of perchlorate (i.e., about 

0.03% of the body’s total goitrogen load). Conversely, when the iodide concentration increases, 

the TIU value increases faster than the decrease in the TIU value from the amount of NIS 

inhibition induced by iodide itself. Therefore, elimination of the iodide term from the 

Tonacchera PEC equation represents a negligible bias in the calculation of the amount of total 

NIS inhibition acting on the body. 

The SPEC equation can be used when the serum molarities of each NIS inhibitor is 

measured and reported. However, serum molarity data for NIS inhibitors is not commonly 

measured or reported in human exposure studies. The oral exposure (i.e., dose) to NIS inhibitors 

is more commonly determined and measured as the weight consumed through ingestion. 

4.3 Oral Perchlorate Equivalent Concentration (OPEC) 

The total NIS inhibitory effect measured upon ingestion of the NIS inhibitors is given by 

the following OPEC equation (concept adapted from Tonacchera 2004; De Groef 2006, p 155): 

OPEC = (Amt of ClO4

-

 Inhibition) + (Amt of NO3

- Inhibition) + (Amt of SCN-

 Inhibition) 

OPEC = grams perchlorate + grams nitrate/150 + 0.5 free SCN-

 x grams thiocyanate/8.8 

OPEC = grams perchlorate + grams nitrate/150 + grams thiocyanate/17.6 

Where: 

Oral inhibition potency of perchlorate = 1 

Oral inhibition potency of nitrate relative to perchlorate = 1/150 

Oral inhibition potency of thiocyanate relative to perchlorate = 0.5/8.8 = 1/17.6 

The above OPEC equation adjusts the relative NIS inhibitor potencies for the following 

three factors: 

1.	 The potency is adjusted to reflect the relationship based on the weights of each NIS 

inhibitor ingested instead of the molarity of each NIS inhibitor in the serum. 

2.	 The potency is also adjusted to take into account the different pharmacokinetic properties 

of each of the NIS inhibitors upon ingestion (i.e., the different absorption and excretions 

characteristics of each NIS inhibitor). 

3.	 The amount of SCN-

 binding to albumin in human blood serum. 

The pharmacokinetic differences are critical in determining the relative NIS inhibition 

potencies of each anion upon ingestion. The ingested absorption and serum half-lives of each 

anion have to be taken into account. Only about 50% of thiocyanate is absorbed in the 

gastrointestinal tract upon ingestion. Meanwhile, 70-90% of ingested perchlorate and 90-100% 

of ingested nitrate is absorbed in the gastrointestinal tract. Furthermore, the half-lives of 

37
 
 

10-P-0101 

perchlorate, thiocyanate, and nitrate are 8 hours, 6 days, and 5 hours, respectively. Thiocyanate 

stays in the serum 18-29 times longer than the other anions. For example, only half of the 

ingested amount of thiocyanate is absorbed upon ingestion, but the amount of thiocyanate 

absorbed stays in the blood serum much longer, to act on and inhibit the NIS. Furthermore, only 

about 0.5 of the total SCN- in human blood serum at typical SCN- concentrations is free to 

interact with the NIS protein. Therefore, the NIS inhibition potency of ingested thiocyanate is 

about 6% (i.e., 0.5 ÷ 8.8 x 100%) – the NIS inhibition potency of ingested perchlorate. The 

essential observation from the pharmacokinetics is that ingested thiocyanate has about onequarter the potency as ingested perchlorate, but thiocyanate is consumed in mg quantities in the 

diet while perchlorate is only consumed in μg quantities (i.e., median is 4.6 μg) in the diet. From 

this preliminary information, thiocyanate appears to contribute the largest amount of NIS 

inhibition in the body. A more detailed analysis of the relative contribution of each NIS inhibitor 

is provided in Section 7.2 of this document. 

4.4 Tonacchera NIS Model of Competitive Inhibition 

 The Tonacchera in vitro NIS Model of Competitive Inhibition calculates the TIU by the 

NIS from the concentration of the following four anions: iodide, perchlorate, nitrate, and 

thiocyanate. The Tonacchera Model is given by the following equation (concept adapted* from 

Tonacchera 2004): 

TIU = constant x [I-

] / (1.22 + (SPEC)) 

Since the constant is not provided, the TIU can be restated as: 

TIU is proportional to [I-

] / (1.22 + ([Perchlorate] + [Nitrate]/240 + [free SCN-]/15) 

where: 

The [ ] of each anion is express in μmol/L units 

The Tonacchera Model is particularly useful because it models the key biological event 

in the toxicity of perchlorate – the uptake of iodide by the thyroid by the NIS. The model 

predicts the uptake of iodide to the simultaneous exposure to all four variables (i.e., iodide, 

perchlorate, thiocyanate, and nitrate) affecting the uptake of iodide. The ability to predict the 

amount of uptake of iodide knowing the body’s total goitrogen load and the body’s iodide 

nutritional status is a powerful tool for assessing the risk from perchlorate exposure. 

The NAS Committee recommends that the key biochemical event (i.e., the inhibition of 

iodide uptake) should be used as the basis of the risk assessment (NAS 2005, p 14, 166, 169). 

Therefore, the TIU is key the biochemical event that is perturbed by the NIS stresssors and 

should be used as the basis for the risk assessment of this public health issue. The mode of 

action identifies that a low TIU during pregnancy and nursing increases the risk of subtle mental 

deficits in the children. However, the cumulative effect of all four NIS stressors on the thyroid 

(i.e, not just perchlorate exposure) determines the TIU level during the critical time period of 

pregnancy and nursing. In other words, the cumulative effect of the four NIS stressors argues 

against perchlorate exposure alone as being directly associated with an adverse outcome. By 

38
 
10-P-0101 

contrast, a low TIU during pregnancy and nursing is associated with an adverse outcome. 

Therefore, the Tonacchera Model allows the TIU to be calculated from the concurrent exposure 

from all four NIS stressors. Furthermore, the Tonacchera Model allows specific adverse effects 

to be associated with specific calculated TIU level. 

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5. Deriving a Reference Dose (RfD) 

The NAS Committee emphasized that its approach for deriving a perchlorate RfD differs 

from the traditional single chemical risk assessment approach (NAS 2005, p 15). A traditional 

single chemical risk assessment derives an RfD from an adverse effect such as a no-observedadverse-effect-level (NOAEL) or a lowest-observed-adverse-effect-level (LOAEL). By contrast, 

the NAS Committee used the unconventional approach of using a nonadverse effect to derive its 

recommended perchlorate RfD. The nonadverse effect was the inhibition of iodide uptake by the 

NIS, which is labeled a no-observed-effect-level (NOEL). The NAS Committee used the NOEL 

identified in the Greer study (Greer 2002) and set the perchlorate exposure level of 0.007 mg/kgday as the POD. The NAS Committee describes its approach of using a NOEL to derive the RfD 

as conservative and health protective (NAS 2005, p 15). 

The NAS Committee also proposed the following mode-of-action model for perchlorate 

toxicity in humans (see below) (NAS 2005, p 167, figure 5-2). The NAS Committee identified 

hypothyroidism as the first adverse effect in the continuum of biological effects. A traditional 

single chemical risk assessment would use the perchlorate dose that just induces hypothyroidism 

(i.e., a LOAEL), but the NAS Committee states that hypothyroidism should not be used as the 

basis of a perchlorate risk assessment (NAS 2005, p 166). Overt hypothyroidism is characterized 

by an elevated TSH level and a below normal T4 level. Furthermore, subclinical hypothyroidism 

is characterized by an elevated TSH level and normal T4 level. Therefore, NAS Committee’s 

mode-of-action model has identified that transient changes of T4, T3, and TSH levels within a 

normal concentration range are nonadverse health effects. 

Source: NAS 2005, p 167, figure 5-2. 

The final step in deriving an RfD is the application of UFs to the POD. The application 

of UFs attempts to account for both uncertainty and the variability in the available data (EPA 

2002, p 4-38, section 4.4.5). The seven UFs that can be potentially applied to a POD depending 

in the nature of the dataset are: interspecies UF, intraspecies UF, LOAEL to NOAEL UF, 

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database UF, subchronic-to-chronic-duration UF, modifying factor, and the Food Quality 

Protection Act. The Act allows a 10x safety factor to protect infants and children from pesticide 

residues. The value of each UF depends on the quality of the studies available, the extent of the 

database, and scientific judgment (EPA 2002, p 4-40, section 4.4.5.1). The NAS Committee 

wrote, “No absolute rules exist for application of the [uncertainty] factors, and professional 

judgment is a large component of their use.” (NAS 2005, p 29). Each one of these UF can have 

a value of 1, 3, or 10. If multiple UFs greater than 1 are used, then the UF values are multiplied 

together (e.g., 10 x 10 x 3 = 300). Since there is overlap in the coverage of uncertainty in the 

UF, the upper limit of total UF applied to a POD should be no more than 3000 (EPA 2002, p 4­

41, section 4.4.5.1). 

The NAS Committee used a POD (i.e., labeled as a NOEL) of 0.007 mg/kg-day identified 

in the Greer study (Greer 2002) and applied a total UF of 10 (i.e., 10x intraspecies UF) to derive 

the NAS Committee’s recommended perchlorate RfD of 0.0007 mg/kg-day as the POD. By 

contrast, EPA used a POD (i.e., labeled as a LOAEL) of 0.01 mg/kg-day from the Argus rat 

study (Argus 2001) and applied a total UF of 300 (i.e., 3x intraspecies UF, 10x LOAEL to 

NOAEL UF, 3x duration UF, and 3x database insufficiency, and a 1x interspecies UF 

(equivalent of omitting the UF)) to derive the EPA draft perchlorate RfD of 0.00003 mg/kg-day 

(EPA 2002a, p 7-20–7-23). The following table summaries the differences between how the 

NAS Committee and EPA derived a perchlorate RfD: 

Perchlorate 

Assessment 

Biological Effect 

Used as the POD 

Critical Study 

and 

Type of POD 

POD Value 

(mg/kg-day) 

Total 

UF 

Proposed 

RFD* 

(mg/kg-day) 

NAS 2005 

Inhibition of iodide uptake 

by the NIS 

Greer 2002 Human Study 

NOEL 

(nonadverse effect) 0.007 10 0.0007 

EPA 2002 

Brain Morphometry, 

Thyroid Histopathology, 

Thyroid hormone changes 

Argus 2001 Rat Study 

LOAEL 

(adverse effect) 0.01 300 0.00003 

* Proposed RfD = POD value ÷ Total UF 

The scientific disagreement on the manner in which to derive the perchlorate RfD centers 

around the following issues: 

•	 Should animal data or human data be used to determine the POD (NAS 2005, 14; EPA 

2002a)? 

•	 Is the inhibition of iodide uptake an adverse or nonadverse effect (Ginsberg 2005; EPA 

2002a, p 7-26, section 7-26)? 

•	 Which UFs should be applied? And if the UF is applied, at what magnitude (i.e., 1, 3, or 

10) (Ginsberg 2005)? 

Depending on the manner in which each of these scientific concerns is addressed, the 

total UF applied to the POD will be different. Therefore, in a traditional single chemical risk 

assessment, the numerical value of the RfD depends significantly on the total UF applied to the 

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POD. The UFs applied and their size is a matter of scientific judgment in order to account for 

uncertainty and variability in the data. 

5.1 Issues with the Single Chemical Risk Assessment of Perchlorate 

A review of every scientific aspect in the perchlorate single chemical risk assessment is 

beyond the capability, resources, and mission of the OIG. The OIG has identified that due to the 

interaction of multiple factors, a cumulative risk assessment approach is needed to characterize 

and address the risk in this public health issue. However, the OIG review specifically comments 

on the following issues relating to a single chemical risk assessment of perchlorate because the 

comments provide insight into the science of perchlorate: 

•	 Is the NAS Committee’s unconventional approach of using a NOEL to derive its 

recommended perchlorate RfD conservative and health protective? And, if so, 

quantify how conservative the NAS recommend perchlorate RfD is as compared to 

using the traditional single chemical risk assessment approach to deriving an RfD? 

•	 Evaluate whether hypothyroidism is the first adverse effect in the continuum of 

biological effects from perchlorate exposure. 

•	 Evaluate the application of UFs to deriving a perchlorate RfD in a single chemical 

risk assessment. 

5.1.1 Defining an RfD 

To evaluate the NAS Committee’s unconventional approach of deriving an RfD, the 

conventional approach of driving an RfD and a strict regulatory definition of an RfD must be 

defined. Since an RfD is part of a risk assessment, the term risk assessment is defined: 

Risk Assessment (in the context of human health): The evaluation of scientific 

information on the hazardous properties of environmental agents (hazard 

characterization), the dose-response relationship (dose-response assessment), and the 

extent of human exposure to those agents (exposure assessment). The product of the risk 

assessment is a statement regarding the probability that populations or individuals so 

exposed will be harmed and to what degree (risk characterization) (EPA 2002; IRIS 

2007). 

As such, a risk assessment is comprised of four parts: hazard characterization, doseresponse assessment, exposure assessment, and risk characterization. The first portion of a risk 

assessment is to determine the hazardous properties of the environmental agent (i.e., perchlorate) 

in a hazard characterization, which is defined: 

Hazard Characterization: A description of the potential adverse health effects 

attributable to a specific environmental agent, the mechanisms by which agents exert 

their toxic effects, and the associated dose, route, duration, and timing of exposure (EPA 

2002; IRIS 2007). 

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The hazard characterization identifies the potential adverse health effects in humans 

resulting from a specific agent. For the health characterization of perchlorate, the NAS 

Committee states that the first adverse health effect in humans is hypothyroidism, which 

precedes any potential for mental deficits in offspring. 

For a single chemical risk assessment, the hazard characterization of only a specific agent 

is a critical limitation that can fatally flaw the risk assessment. Multiple agents exerting their 

toxic effects through the same mechanism are not considered together. This limitation can be 

without consequence to the single chemical risk assessment if the single chemical is the 

dominant factor causing the adverse effect. However, if the single chemical being studied is 

only a minor factor among other stronger factors, this limitation in a single chemical risk 

assessment can seriously distort the risk characterization. The OIG’s use of cumulative risk 

assessment will demonstrate the latter to be the situation with perchlorate. 

The second part of a single chemical risk assessment is the dose-response assessment, 

which is defined: 

Dose-Response Assessment: A determination of the relationship between the magnitude 

of an administered, applied, or internal dose and a specific biological response. Response 

can be expressed as measured or observed incidence or change in a level of response, 

percent response in groups of subjects (or populations), or the probability of occurrence 

or change in level of response within a population (EPA 2002). 

A dose-response assessment identifies that dose that causes an increased occurrence of a 

particular biological event in the test subjects. For perchlorate, the NAS Committee identified 

that a dose of 0.007 mg/kg-day of perchlorate does not statistically inhibit the uptake of iodide 

by the NIS in adult test subjects as compared to controls subjects. 

To conduct the third portion of a risk assessment (i.e., the exposure assessment), the RfD 

needs to be calculated from the dose-response relationship identified in the dose-response 

assessment. RfD is defined: 

Reference dose (RfD): An estimate of a daily oral exposure for a given duration to the 

human population (including susceptible subgroups) that is likely to be without an 

appreciable risk of adverse health effects over a lifetime. It is derived from a benchmark 

dose lower confidence limit (BMDL), a NOAEL, a LOAEL, or another suitable point of 

departure, with uncertainty/variability factors applied to reflect limitations of the data 

used (EPA 2002; IRIS 2007). 

Notice that the definition of an RfD is based on avoiding adverse health effects and is 

derived from a dose associated with an adverse effect (i.e., BMDL, NOAEL, LOAEL, or POD). 

The definition of BMDL, NOAEL, LOAEL, and POD are defined below and all specifically 

include the use of adverse effect: 

BMDL: A statistical lower confidence limit on the dose or concentration at the 

benchmark dose (BMD) or benchmark concentration (BMC) respectively (EPA 2002). 

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BMD or BMC: A dose or concentration that produces a predetermined change in 

response of an adverse effect . . . compared to the background (EPA 2002). 

NOAEL: The highest exposure level at which there are no biologically significant 

increases in the frequency or severity of adverse effect between the exposed population 

and its appropriate control . . . (EPA 2002; IRIS 2007). 

LOAEL: The lowest exposure level at which there are biologically significant increases 

in frequency or severity of adverse effects between the exposed population and its 

appropriate control group (EPA 2002; IRIS 2007). 

POD: The dose-response point that marks the beginning of a low-dose extrapolation. 

This point can be the lower-bound on dose for an estimated incidence or a change in 

response level from a dose-response model (BMD), or a NOAEL or LOAEL for an 

observed incidence, or change in level of response (EPA 2002; IRIS 2007). 

Therefore, an RfD is defined by the adverse effect from which it is derived. The RfD is a 

dose that is typically one to three orders of magnitude (i.e., 10 to 1000 times) below the NOAEL 

or LOAEL from with it was derived by the use of uncertainty/variability factors applied to reflect 

limitations of the data used. Thus, the RfD is set at a dose that is below an exposure that is likely 

to cause the observed adverse health effects in even the most sensitive group. 

The exception to the use of an adverse effect to derive an RfD is that the risk assessment 

guidance allows the use of the immediate precursor to the adverse effect. This is seen in the 

definition of a critical effect: 

Critical Effect: The first adverse effect, or its known precursor, that occurs to the most 

sensitive species as the dose rate of an agent increases (EPA 2002; IRIS 2007). 

In regard to perchlorate, since the NAS Committee identified hypothyroidism as the first 

adverse effect, its immediate precursor in the NAS mode-of-action model (NAS 2005, p 167, 

figure 5-2) is listed as thyroid hypertrophy or hyperplasia, but hypertrophy and hyperplasia are 

not typically measured in epidemiological studies. Since overt hypothyroidism is characterized 

by an elevated TSH level and a below normal T4 level, and subclinical hypothyroidism is 

characterized by an elevated TSH level and normal T4 level, the immediate precursor to 

hypothyroidism could be considered a perchlorate exposure that induces a statistically significant 

change in thyroid hormones levels in the exposed group as compared to the control group. 

However, the NAS Committee did not derive its RfD from either hypertrophy, 

hyperplasia, or thyroid hormone changes. The NAS Committee derived its perchlorate RfD from 

the NOEL observed from the inhibition of iodide uptake by the NIS in the Greer study. A NOEL 

is defined as: 

NOEL: 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 (EPA 2002; IRIS 2007). 

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In the NAS Committee’s mode-of-action mode, the inhibition of iodide uptake by the 

thyroid is three biological steps before hypothyroidism. Furthermore, the inhibition of iodide 

uptake in the thyroid is not an immediate precursor to hypothyroidism. When the biology allows 

for the identification of multiple NOAELs, each associated with different biological response, 

the highest NOAEL is used for regulatory purposes. For perchlorate, this means a NOAEL 

identified for changes in thyroid hormones (i.e., the immediate precursor to hypothyroidism). 

This concept is included in the following NOAEL definition used by EPA’s Office of 

Communications, Education, and Public Affairs (OCEPA): 

EPA OCEPA NOAEL: An exposure level at which there are no statistically or 

biologically significant increases in the frequency or severity of adverse effects between 

the exposed population and its appropriate control; some effects may be produced at this 

level, but they are not considered as adverse, or as precursors to adverse effects. In an 

experiment with several NOAELs, the regulatory focus is primarily on the highest one, 

leading to the common usage of the term NOAEL as the highest exposure without 

adverse effects. 

Therefore, the NAS Committee’s unconventional derivation of an RfD from the 

inhibition of iodide uptake (i.e., NOEL) does not meet the strict definition of an RfD in that it is 

derived from an adverse effect. Since the NAS Committee’s recommended RfD was derived 

from a biological response several steps before the adverse effect, the POD value used is at a 

dose below a NOAEL or LOAEL that would be conventionally used for deriving an RfD. Thus, 

in our opinion, the NAS Committee used a conservative approach of using a NOEL to derived its 

RfD, but the degree of conservatism (i.e., quantitatively) is not identified because the value of a 

conventionally derived perchlorate RfD is not known since adverse health effects have not been 

clearly demonstrated in any human population exposed to perchlorate (NAS 2005, p 177). 

The NAS Committee also states its recommended RfD is health protective, but evaluating 

this is difficult because the amount of TIU that causes sufficient thyroid stress in pregnant 

women to induce mental deficient in their children is not defined in the single chemical risk 

assessment approach. Furthermore, following the single chemical risk assessment process does 

not guarantee a health protective RfD. By contrast, the application of a cumulative risk 

assessment approach expands the understanding of the stressors that affect this public health 

issue and provide a clearer, more complete picture of this public health issue for making riskmanagement decisions. Therefore, the cumulative risk assessment results can be used to 

evaluate whether the NAS Committee-recommended RfD is health protective. 

5.1.2 Evaluation of the Application of UFs for Deriving the Perchlorate RfD 

The NAS Committee used a nonadverse POD of 0.007 mg/kg-day identified from the 

human exposure to perchlorate in the Greer study (Greer 2002) to derive its recommended 

perchlorate RfD. By comparison, the EPA used an adverse POD of 0.01 mg/kg-day identified in 

the Argus rat study to derive EPA’s draft RfD. Note that the respective PODs of 0.007 mg/kgday and 0.01 mg/kg-day are essentially the same. Therefore, the difference in the NAS and EPA 

RfDs arise from the selection of which UFs are applied (i.e., interspecies UF, intraspecies UF, 

LOAEL to NOAEL UF, database UF, subchronic-to-chronic-duration UF, modifying factor) and 

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the magnitude of each UF applied (i.e., 1, 3, or 10). The NAS Committee used a total UF of 10 

while EPA used a total UF of 300. 

The EPA risk assessment guidance indicates the preference to use human data over 

animal data to set a POD. EPA risk assessment guidance states, “Human or animal data can be 

used to derive an RfD, but when adequate and sufficient human data on the most sensitive effect, 

the EPA guidance states that the human data should be used” (EPA 2002, p 4-12). Human data 

is preferred because it minimizes the uncertainty of extrapolating adverse effects observed in 

animal studies to potential effects in humans. This uncertainty is the source and reason an 

interspecies UF is often applied when deriving an RfD from animal data (EPA 2002, p 4-42, 

section 4.4.5.2). Although neither dataset is ideal because the amount of iodide inhibition that 

induces subtle mental deficits in children during gestation is not identified by these studies, 

human data are preferred over animal data. 

The use of human data is critical for applying a cumulative risk assessment approach to 

this public health issue. In animal studies, the ability to test the cognitive abilities of the exposed 

animals is very crude and insensitive to subtle mental deficits. For example, how do you 

measure a subtle loss of verbal comprehension in a rat? Or, how do you measure a subtle 

decrease in the attentiveness of a rat? By comparison, measuring subtle mental deficits such as 

verbal comprehension or ADHD in human children is relatively straightforward. The human 

exposure to each of the four NIS stressors can be measured or estimated for use in a cumulative 

risk assessment (i.e., varying the exposure of the four NIS stressors in an animal study is too 

complicated, expensive, and relatively insensitive to identifying the endpoint of subtle mental 

deficits). The Tonacchera Model allows the combined effect on the NIS to be determined and 

identified into a single variable, TIU. In contrast to the limitations of a single chemical risk 

assessment, a cumulative risk assessment can identify the %TIU in pregnant women that is 

associated with subtle mental deficits in their children. Therefore, for this public health issue, 

animal data are not an adequate substitute for human data (i.e., animal data can supplement, but 

not replace, human data for this public health issue). 

The NAS Committee used a nonadverse POD to derive its recommended perchlorate 

RfD. However, not everyone in the scientific community agrees that the inhibition of iodide 

uptake is a nonadverse effect (Ginsberg 2005; EPA 2002a, p 7-26, section 7.1.5.1). 

Toxicologists can have different interpretations of what constitutes an adverse effect (Dorato 

2005). An approach to classifying effects as adverse or nonadverse are discussed in Dorato’s 

paper (Dorato 2005, figure 5). If the inhibition of iodide uptake is considered an adverse effect 

(e.g., a LOAEL), a LOAEL to NOAEL UF would be applied with a magnitude of 3 or 10 

(Ginsberg 2005). So, the issue of whether the inhibition of iodide uptake is adverse or 

nonadverse simply affects the amount of total UFs to be applied to the POD to derive the RfD 

(see next paragraph – the impact of total UF on this public health issue). 

The evaluation of the appropriate selection and magnitude of each UF to be applied to the 

derivation of a perchlorate RfD is difficult due to the lack of a clear scientific consensus of their 

application to the perchlorate dataset. The value of each UF depends on the quality of the studies 

available, the extent of the database, and scientific judgment (EPA 2002, p 4-40, section 4.4.5.1). 

The NAS Committee wrote, “No absolute rules exist for application of the [uncertainty] factors, 

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and professional judgment is a large component of their use.” (NAS 2005, p 29). However, the 

total UF used directly affects the calculated RfD value and any resulting regulatory exposure 

limits set from the RfD. The scientific considerations center around which UF to apply and at 

what magnitude. However, there is no scientific discussion if the application of UFs to the POD 

accomplishes the intent of an RfD. An RfD sets an oral exposure limit that is likely to prevent 

adverse health effects from occurring in the human population over a lifetime. 

The perchlorate RfD sets an exposure limit to only one of four known NIS stressors. 

Even if the perchlorate RfD is never exceeded in a population, the combined effect from various 

exposure level combinations from the other three uncontrolled NIS stressors (i.e., lack of iodide, 

thiocyanate, and nitrate) can still generate an unacceptable adverse health effects in humans. All 

four NIS stressors conspire to limit the amount of iodide uptake in the thyroid, which initiates all 

subsequent adverse health effects, not just perchlorate exposure. The use of the Tonacchera 

Model in a cumulative risk assessment approach can identify the %TIU(LOAEL) and %TIU(NOAEL) 

in pregnant women that is associated with subtle mental deficits in their children. The use of 

UFs should be applied to the %TIU(LOAEL) or %TIU(NOAEL) to set a %TIU(RfD) exposure limit 

(i.e., the integrated effect of all four NIS stressors) and not the POD for perchlorate. The mode 

of action identifies that adverse effects are avoided if the amount of TIU in the thyroid is 

sufficiently high. Limiting exposure of only perchlorate does not guarantee an acceptable TIU 

level. Only by managing the exposure to all four NIS stressors is the TIU level guaranteed to be 

a sufficiently high %TIU to avoid adverse effects. 

The demonstration of this principle can be seen in the cumulative risk assessment (see 

Section 9.3). When the total applied UF value is increased from 10 to 500 and is applied only to 

the perchlorate exposure, the corresponding DWEL shifts from 24.5 ppb and 0.5 ppb, 

respectively. The calculated increase in %TIU in an adult is estimated to be 0.4% when the 

perchlorate DWEL is lowered from 24.5 ppp to 0.5 ppb. In a pregnant woman, our analysis 

estimates a 1.0% increase in the %TIU when the perchlorate DWEL is lowered from 24.5 ppb to 

6.1 ppb (see Section 9.5). A change of 1.0%TIU in pregnant women is below the statistical 

detection in a human radioactive iodide uptake exposure study (e.g, the Greer study). Our 

cumulative risk assessment estimates that the %TIU would have to fall 50% from a healthy 

iodide uptake level for pregnant women to potentially start inducing subtle mental deficits in 

their children. Therefore, the particular total UF (i.e., 10 to 500) applied to the perchlorate POD 

in a single chemical risk assessment is not particularly significant in maintaining a sufficient 

iodide uptake during pregnancy. By contrast, our analysis indicates that the application of UF 

needs to be applied to the %TIU(NOAEL) level, because a low %TIU (and not perchlorate 

exposure only) is associated with an adverse outcome. Therefore, the use of a cumulative risk 

assessment approach is essential to accurately characterize and to understand the risks affecting 

this public health issue and to formulate an effective response(s) to the problem. The cumulative 

risk assessment indicates that the dominant stressor in this public health issue is the lack of 

iodide stressor, and because of iodide deficiency during pregnancy, about 29% of pregnant 

women are below %TIU(NOAEL). 

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5.1.3 First Adverse Effect: Hypothyroidism or Hypothyroxinemia 

The NAS Committee identified hypothyroidism as the first adverse effect, but 

recommended against using hypothyroidism as the basis for a perchlorate risk assessment (NAS 

2005, p 166-67). The fetus needs a sufficient supply of T4 during gestation for proper brain 

development. The fetus is entirely dependent on the maternal supply of T4 through midgestation (Glinoer 2005, p 1095) and is still sensitive to maternal supply thereafter. Maternal 

hypothyroidism is toxic to the fetus because it causes a decreased maternal supply of T4 during 

gestation. The adverse effects on the fetus from maternal hypothyroidism are reported in a 1999 

New England Journal of Medicine study. This study reported on maternal thyroid deficiency and 

the subsequent neuropsychological development of the children (Haddow 1999). The study 

identified 47 pregnant women with elevated TSH (i.e., > 6 ul/ml) and another 15 pregnant 

women with both elevated TSH and low T4 levels. Of the 48 pregnant women who did not 

receive treatment for their thyroid deficiency, the full-scale intelligence quotient (IQ) of their 

children averaged 7 points lower (p = 0.005) than the 124 matched control children. 

Hypothyroidism is an adverse effect from an extremely low uptake of iodide by the 

thyroid, but hypothyroidism is not the first adverse effect from perchlorate exposure. 

Hypothyroxinemia is the first adverse effect from a low uptake of iodide by the thyroid. Iodide 

deficiency and excess NIS inhibition (i.e., perchlorate exposure) act through the same 

mechanism (i.e., each result in a low uptake of iodide by the thyroid). The Tonacchera Model 

indicates that the amount of iodide taken up into the thyroid by the NIS is directly related to the 

amount of iodide in the blood. If the diet is poor in iodide, the amount of iodide uptake will be 

low, regardless of how much or how little NIS inhibition is occurring. Therefore, the lack of 

iodide in the diet has the same mechanism of toxicity and outcome as a high NIS inhibition level; 

not enough iodide is taken up by the thyroid for the sufficient production of thyroid hormones. 

Therefore, the adverse effects caused by iodide deficiency are the same adverse effects that 

would be expected from a high NIS inhibition level when not enough iodide is taken up by the 

thyroid. 

Iodide deficiency is frequently and incorrectly associated with hypothyroidism and 

increased TSH (Obregon 2005, p 918). The TSH-independent autoregulation is often 

overlooked, or actually not known to younger Western-trained physicians (Obregon 2005, 

p 918). Atrophy of the thyroid and overt hypothyroidism occur only when iodide deficiency is 

accompanied by a high goitrogen load and/or selenium deficiency (Obregon 2005, p 918). 

Clinical or subclinical hypothyroidism is not observed in uncomplicated iodide deficiency 

(Obregon 2005, p 918). By contrast, iodide deficiency (i.e., the lack of an adequate uptake of 

iodide by the thyroid) induces hypothyroxinemia, a thyroid condition characterized by a 

decreased T4 serum level and a normal or slightly elevated T3, without an increase in TSH levels 

(i.e., TSH levels are normal) (Obregon 2005, p 918). Mild to moderate iodide deficiency is the 

most widespread cause of maternal hypothyroxinemia (Morreale de Escobar 2004, p U25). The 

decrease in T4 in pregnant women with hypothyroxinemia in the first 20 weeks of pregnancy is 

associated with mental deficits and an increased frequency of ADHD in their children 

(Vermiglio 1994). Therefore, maternal hypothyroxinemia induces fetal brain damage through 

the same cause as maternal hypothyroidism – a decreased maternal supply of T4. 

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5.1.4 Comparison of the NAS Unconventional RfD with a Conventionally Derived 

Excess NIS Inhibition RfD 

The NAS Committee states that adverse health effects have not been clearly 

demonstrated in any human population exposed to perchlorate (NAS 2005, p 177). This lack of 

clear demonstration prevents the calculation of a perchlorate RfD using the conventional single 

chemical risk assessment approach of deriving an RfD from a NOAEL or LOAEL. However, 

perchlorate is only one of three NIS inhibitors continuously acting on the thyroid to prevent the 

uptake of iodide. The other two ubiquitously consumed NIS inhibitors are thiocyanate and 

nitrate. The Tonacchera Model identifies the relative potency factor for each of the three NIS 

inhibitors relative to perchlorate and identifies the interaction of the chemical mixture as simple 

competitive interaction (Tonacchera 2004). There is no evidence of synergism or antagonism in 

chemical mixtures of these three NIS inhibitors. Therefore, the total amount of NIS inhibition 

acting on the thyroid is the combined contribution of each anion on a molar potency adjusted 

basis (i.e., a dose-addition method). 

The principle of dose addition can be utilized to independently calculate an excess NIS 

inhibition RfD and compare it to the NAS-recommended perchlorate RfD. Unlike perchlorate in 

which adverse effects have not been documented in humans, adverse effects have been 

documented in human populations exposed to excess amounts of the other two NIS inhibitors, 

thiocyanate and nitrate. Since the NIS inhibition from thiocyanate and nitrate are 

indistinguishable from the NIS inhibition from perchlorate (Tonacchera 2004), the amount of 

NIS inhibition in these human populations can be measured and expressed mathematically as a 

PEC. Then the conventional single chemical risk assessment approach can use the observed 

NOAELs and LOAELs in these human populations to independently derive an excess NIS 

inhibition RfD (i.e., a descriptive name for what the perchlorate RfD represents). The excess 

NIS inhibition RfD (i.e., which was derived through the conventional approach of using a 

NOAEL or LOAEL) can be compared to the NAS-recommended perchlorate RfD (i.e., which 

was derived through a unconventional approach of using a NOEL) to quantify how conservative 

the NAS-recommended perchlorate RfD might be. 

The OIG identified the following three epidemiological studies to calculate an excess NIS 

inhibition RfD in which adverse and nonadverse thyroid effects can be observed in human 

populations exposed to excess amount of the NIS inhibitors thiocyanate and nitrate: 

1.	 Severe hypothyroxinemia can be observed in the electroplating workers exposed to 

cyanide resulting in an excess exposure to the NIS inhibitor thiocyanate (Banerjee 1997). 

(See Section 5.1.4.1). 

2.	 Hypothyroxinemia can be observed in women consuming thiocyanate-preserved cow’s 

milk, which resulted in an excess exposure to the NIS inhibitor thiocyanate (Banerjee 

1997b). (See Section 5.1.4.2). 

3.	 Hypertrophy (i.e., an increase in the size of the thyroid) can be observed in children 

consuming nitrate-contaminated water, which resulted in an excess exposure to the NIS 

inhibitor nitrate (Tajtáková 2006). (See Section 5.1.4.3). 

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The NAS Committee states that transient changes in serum thyroid hormones and TSH 

concentrations are not adverse health effects (NAS 2005, p 166). Furthermore, the NAS 

Committee states that the serum thyroid hormone concentrations should not be used as the POD 

for the risk assessment (NAS 2005, p 169). The OIG Analysis of the thyroid function concurs 

with this assessment. The thyroid is in a continuous dynamic process (i.e., homeostasis) to 

maintain the serum T4 and T3 level within a normal range under ever-changing levels of 

exposure to the four NIS stressors. Transient changes in serum thyroid hormones and TSH 

concentrations are a reflection of the thyroid working to maintain equilibrium. In contrast to 

using transisent changes in serum thyroid hormone and TSH concentrations as the POD, the OIG 

Analysis identified two thiocyanate exposure studies (i.e., 1. and 2. from above) in which a longterm exposure to excess thiocyanate exceeded the thyroid’s ability to adapt and maintain a serum 

T4 level within a normal range. This is appropriate because the mode of action for this public 

health issue identifies that the failure of the thyroid to maintain an adequate serum T4 level 

during pregnancy and lactation induces the adverse effects in the offspring. Our analysis 

identified a study (i.e., 3. from above) in which a long-term NIS stressor exposure to nitrate 

resulted in hypertrophy in the school-aged children. 

50
 
 

 

10-P-0101 

5.1.4.1 Calculation of an Excess NIS Inhibition RfD Using the Adverse Thyroid 

Health Effects Observed in Electroplating Workers Exposed to Cyanide in Adult 

Men 

Background 

Sodium cyanide and potassium cyanide are salts used in the electroplating industry. The 

cyanide containing electroplating baths caused occupational exposure of the electroplating 

workers to cyanide. Once cyanide is absorbed into the body, about 80% of absorbed cyanide is 

metabolized to thiocyanate (SCN-) by the sulfurtransferase enzyme, rhodanese (WHO 2004). 

Description of Banerjee’s Thiocyanate Study in Adult Males 

Of 201 male workers in the plant, 35 male workers had worked in the electroplating 

process area for at least 5 consecutive years (i.e., the exposed group) (Banerjee 1997). Another 

35 male workers who worked outside the manufacturing building were matched for age and 

dietary habits (i.e., nonexposed group – control). All subjects were selected randomly from 

among employees who did not use tobacco products and who had no history of thyroid disease. 

Five mls of blood were collected from each subject. The blood serum was tested for 

serum T4, T3, TSH, and thiocyanate. 

Iodide Nutritional Status 

The iodide nutritional status of the test subjects was not evaluated in this study. 

Specifically, no urinary samples were taken to measure iodide excretion levels in this study. 

Banerjee’s Thiocyanate Study Results 

Both the T4 and T3 hormone levels in the exposed workers were all statistically lower 

(i.e., p > 0.05) than the nonexposed workers (i.e., the control group). Both T4 and T3 hormone 

levels in the exposed workers are below the normal range for these thyroid hormones. The 

exposed workers’ TSH value is statistically higher (i.e., p > 0.05) than the nonexposed workers. 

However, the exposed workers’ TSH levels were elevated over the controls, but within the 

normal range of 0.2 to 4.0 μU/ml. The following table summaries the study results: 

Study Group 

Thiocyanate 

(μmol/L) 

T4 

(μg/dL) 

T3 

(μg/dL) 

TSH 

(μU/ml) 

35 Nonexposed Workers 

(all nonsmokers) 90.8 ± 9.02 6.09 ± 0.601 111.0 ± 9.3 1.20 ± 0.301 

35 Exposed Workers 

(all nonsmokers) 316 ± 15.0* 3.81 ± 0.318† 57.2 ± 8.1† 2.91 ± 0.20† 

Normal Ranges Cited in the 

Manufacturers Test Kits 5.5 to 13.5 60 to 200 0.2 to 4.0 

* p < 0.01 

† p < 0.05 

Source: Banerjee 1997, table 1. 

51 
 

 

 

 

 

 

10-P-0101 

Amount of Excess Thiocyanate 

The nonexposed workers (all nonsmokers) had a serum thiocyanate concentration of 90.8 

± 9.02 μmol/L. The exposed workers had a serum thiocyanate concentration of 316 ± 15.0 

μmol/L. Therefore the amount of excess thiocyanate measured in the serum was 225.2 μmol of 

SCN-/L (i.e., 316 μmol/L - 90.8 μmol/L). 

Amount of Excess NIS Inhibition in the Exposed Workers 

The amount of excess NIS inhibition from thiocyanate in the exposed workers is 

converted to the SPEC (concept taken from Tonacchera 2004): 

SPEC = (Amt of ClO4

-

 Inhibition) + (Amt of NO3

-

 Inhibition) + (Amt of SCN- Inhibition) 

SPEC = [Perchlorate] + [Nitrate] /240 + ([total serum SCN-] x 0.5) /15 

SPEC = [Perchlorate] + [Nitrate] /240 + [free SCN-

] /15 

Where: [ ] is molarity 

Serum inhibition potency of perchlorate = 1 

Serum inhibition potency of nitrate relative to perchlorate = 1 / 240 

Serum inhibition potency of free thiocyanate relative to perchlorate = 1 / 15 

[free SCN- ] = [total serum SCN-

] x 0.5 free SCN- per total serum SCNHowever, the serum molarity concentration for perchlorate and nitrate are neither 

measured nor reported in the Banerjee study (i.e., they are potentially confounding factors). 

Assuming the perchlorate and nitrate exposure in the Banerjee test subjects is constant between 

the exposed workers and the nonexposed workers (i.e., controls). Then, the SPEC equation can 

be simplified to express only the excess amount of NIS inhibition from the thiocyanate. Thus: 

Excess SPEC(Exposed workers) = ([excess SCN-] x 0.5) ÷ 15 

= (225.2 μmoles of SCN-/L x 0.5) ÷ 15 

 = 7.51 μmol/L SPEC 

Equivalent Amount of Perchlorate Ingestion Corresponding to the Excess SPEC 

The Clewell perchlorate physiologically based pharmacokinetic (PBPK) model is used to 

calculate the external perchlorate exposure (mg/kg-day) from the excess SPEC observed in the 

exposed workers in the Banerjee test subjects (Clewell 2007). The excess SPEC of 7.51 μmol/L 

SPEC must be converted into μg/L SPEC unit for use in the Clewell Perchlorate PBPK Model. 

 μg/L SPEC(Exposed workers) = 7.51 μmol/L SPEC x 99.45 μg perchlorate/μmol 

= 747 μg/L SPEC(Exposed workers) or 0.747 mg/L SPEC(Exposed workers) 

The external perchlorate dose required to generate the amount of excess NIS inhibition 

observed in the exposed workers is calculated using the Clewell PBPK model as follows: 

52
 
 

 

 

10-P-0101 

 Ext. ClO4- Dose = 0.747 mg/L SPEC(Exposed workers) x 1.0 mg/kg-day

 1.0 mg/L 

 = 0.75 mg/kg-day (rounded) 

The exposed workers in the Banerjee study were unable to maintain a normal T4 or T3 

thyroid hormone level while still maintaining a TSH level in the normal range (refer to table 

above). Overt hypothyroidism is characterized by an elevated TSH and below normal T4 while 

subclinical hypothyroidism is characterized by an elevated TSH and normal T4. However, 

hypothyroxinemia is a less severe thyroid condition and is a common condition in pregnant 

women characterized by low maternal fT4 levels with normal TSH levels (Kooistra 2006). 

Therefore, the exposed workers’ thyroid hormone levels could be described as severe 

hypothyroxinemia. Maternal hypothyroxinemia (i.e., during pregnancy) is documented to be 

associated with mental deficits (e.g., ADHD) in the children of those mothers (Vermiglio 2004). 

The mechanism of fetal brain damage from maternal hypothyroxinemia is the same as maternal 

hypothyroidism (i.e., an insufficient maternal supply of T4 to the fetus during gestation). 

Therefore, although hypothyroxinemia is not a permanent adverse effect in adult males, maternal 

hypothyroxinemia is an adverse effect in the most sensitive populations, pregnant women, 

fetuses, and nursing infants. Thus, the OIG has identified the observed severe hypothyroxinemia 

in the Banerjee study exposed workers to be an adverse effect (i.e., if severe hypothyroxinemia 

were to occur in pregnant woman population) from which an excess NIS inhibition RfD can be 

calculated from. 

The excess thiocyanate measured in the exposed workers is converted by the use of the 

Tonacchera Model and the Clewell perchlorate PBPK model to calculate an external perchlorate 

dose that corresponds to the LOAEL of NIS inhibition in an adult male human. In other words, 

an external perchlorate exposure of 0.75 mg/kg-day (or about 55 mg/day for a 70 kg adult male) 

should generate the same thyroid effects (i.e., severe hypothyroxinemia) observed in the exposed 

workers in the Banerjee study. 

Calculation of an Excess NIS Inhibition RfD from the Excess Thiocyanate 

Exposure 

The severe hypothyroxinemia observed in the Banerjee exposed workers is used to 

identify the LOAEL for the calculation of the excess NIS inhibition RfD. Therefore, the 

observed LOAEL in an adult male is: 

LOAEL(Exposed workers) = 0.75 mg/kg-day 

The calculation of an NOAEL from a LOAEL is typically accomplished by applying a 

UF of 10 to the LOAEL (EPA 2002, p 4-44): 

NOAEL(Exposed workers) = 0.75 mg perchlorate equivalent/kg-day / 10 UF 

= 0.075 mg perchlorate equivalent/kg-day 

Since the exposed workers are all men, who are less sensitive than women to adverse 

thyroid effects, a full UF of 10 is applied to the NOAEL to account for the intraspecies factor to 

53
 

 

10-P-0101 

protect the most sensitive populations. The application of a 10 UF in this calculation is 

analogous to the NAS Committee applying a total UF of 10 to the NOEL to protect the most 

sensitive population. The NAS Committee used a NOEL to determine the RfD from the excess 

perchlorate consumption in the Greer study and a 10 UF was applied to it to derive NASrecommended perchlorate RfD (NAS 2005, p 16). The OIG is using a UF of 10 for these 

calculations to allow for the direct comparison of the excess NIS inhibition RfD with the NASrecommended perchlorate RfD of 0.0007 mg/kg-day. Therefore, the excess NIS inhibition RfD 

(from excess SCNexposure) is calculated as follows: 

Excess NIS Inhibition RfD(Adult males) = 0.075 mg perchlorate equivalent/kg-day / 10 UF

 = 0.0075 mg/kg-day 

The calculated excess NIS inhibition RfD from excess SCN- exposure in adult males is 

0.0075 mg/kg-day. EPA’s perchlorate RfD is 0.0007 mg/kg-day obtained from the NAS 

Committee. The calculated excess NIS inhibition RfD(Adult males) is 10.7 times greater than the 

NAS-recommended perchlorate RfD. 

The advantage of determining the excess NIS inhibition RfD is because it used a 

conventional risk assessment approach of deriving an RfD by using a LOAEL observed in a 

human population. The NAS Committee describes its own approach of deriving an RfD from a 

NOEL as being an unconventional approach, but characterizes it as being a “conservative, 

health-protective approach to the perchlorate risk assessment” (NAS 2005, p 15). The OIG’s 

conventional approach for deriving a perchlorate RfD independently supports the NAS 

Committee’s statement that its recommended perchlorate RfD is conservative. The excess NIS 

inhibition RfD(Adult males) observed in the Banerjee thiocyanate study of electroplating workers 

indicates that the NAS-recommended perchlorate RfD is conservative by a factor of 10.3. 

54
 
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5.1.4.2 Calculation of an Excess NIS Inhibition RfD Using the Adverse Thyroid 

Health Effects from the Ingestion of Thiocyanate-Preserved Cow’s Milk by Adult 

Women 

Background 

In Calcutta, India, local dairies add 30-50 mg/L of thiocyanate to preserve cow’s milk in 

order to activate the lactoperoxidase-thiocyanate-hydrogen peroxide system (LP system). The 

LP system forms the hypothiocyanite anion (OSCN-

), which acts as a bacteriostat to retard the 

growth of bacteria. The subsequent ingestion of thiocyanate-preserved cow’s milk causes a 

relatively high thiocyanate exposure to the consumer. 

Description of Banerjee’s Thiocyanate Study in Adult Women 

Thirty-five women who had consumed 250 ml/day of thiocyanate-preserved milk for 

more than 5 consecutive years were designated as the exposed group (Banerjee 1997b). Another 

35 women who consumed the same quantity of nonpreserved raw milk were designed the control 

group (i.e., the nonexposed group). The control group was matched for age and dietary habits. 

All subjects were selected randomly from a population of similar socioeconomic status and 

uniform dietary pattern. Furthermore, all test subjects did not use tobacco products and had no 

history of thyroid disease. 

Five mls of blood were collected from each subject. The blood serum was tested for 

serum T4, T3, TSH, and thiocyanate. Iodide levels were measured by urinary iodide 

concentration (UIC). 

Iodide Nutritional Status 

The iodide nutritional status of the test subjects was evaluated in this study by UIC. The 

UIC of the exposed women was found to be 115 μg/L (SE 8.5). The UIC of the control group 

was found to be 123 μg/L (SE 7.8). The difference in the UICs between the two groups was not 

statistically significant. 

Banerjee’s Thiocyanate Study Results 

Hypothyroxinemia is a thyroid condition characterized by below normal T4 and normal 

T3 and TSH levels. Hypothyroxinemia was observed in thiocyanate-exposed female in the 

Banerjee adult female thiocyanate study (Banerjee 1997b). The thiocyanate-exposed women 

were measured to have below normal T4, and both normal T3 levels and statistically elevated 

TSH levels, but the TSH levels were still in the normal range. This level of hypothyroxinemia is 

less severe than the hypothyroxinemia observed in the Banerjee adult male thiocyanate study 

(Banerjee 1997). The exposed females were measured to have a serum thiocyanate exposure of 

230 ± 10.0 μmol/L. The control women were measured to have a serum thiocyanate exposure of 

90.8 ± 9.0 μmol/L. The observations of the Banerjee study are summarized below: 

55
 
 

 

 

 

 

 

10-P-0101 

Study Group 

Thiocyanate 

(μmol/L) 

T4 

(nmol/L) 

T3 

(nmol/L) 

TSH 

(μU/ml) 

35 Nonexposed Females 

(all nonsmokers) 90.8 ± 9.0 125.4 ± 11.5 1.71 ± 0.16 1.09 ± 0.28 

35 Exposed Females 

(drank SCN­

 preserved milk) 230.0 ± 10.0* 87.8 ± 6.6* 2.39 ± 0.32 2.49 ± 0.20* 

Normal Ranges Cited in the 

Manufacturers Test Kits 110 to 279 0.93 to 3.12 0.2 to 4.0 

* p < 0.01 

Source: Banerjee 1997b, table 1. 

Amount of Excess Thiocyanate 

The control women had a serum thiocyanate concentration of 90.8 μmol/L. The exposed 

women had a serum thiocyanate concentration of 230 μmol/L. Therefore, the amount of excess 

thiocyanate measured in the serum was 139.2 μmol of SCN-

/L (i.e., 230 μmol/L - 90.8 μmol/L). 

Amount of Excess NIS Inhibition in the Exposed Women 

The amount of excess NIS inhibition from thiocyanate in the exposed workers is 

converted to the SPEC (concept taken from Tonacchera 2004): 

SPEC = (Amt of ClO4

-

 Inhibition) + (Amt of NO3

-

 Inhibition) + (Amt of SCN- Inhibition) 

SPEC = [Perchlorate] + [Nitrate] /240 + ([total serum SCN-] x 0.5) /15 

SPEC = [Perchlorate] + [Nitrate] /240 + [free SCN-

] /15 

Where: [ ] is molarity 

Serum inhibition potency of perchlorate = 1 

Serum inhibition potency of nitrate relative to perchlorate = 1 / 240 

Serum inhibition potency of free thiocyanate relative to perchlorate = 1 / 15 

[free SCN- ] = [total serum SCN-

] x 0.5 free SCN- per total serum SCNHowever, the serum molarity concentration for perchlorate and nitrate are neither measured 

nor reported in the Banerjee study (i.e., they are potentially confounding factors). Assuming the 

perchlorate and nitrate exposure in the Banerjee test subjects is constant between the exposed 

workers and the nonexposed workers (i.e., controls), then the SPEC equation can be simplified to 

express only the excess amount of NIS inhibition from the thiocyanate. Thus: 

Excess SPEC(Exposed workers) = ([excess SCN-] x 0.5) ÷ 15 

= (139.2 μmoles of SCN-

/L x 0.5) ÷ 15 

 = 4.64 μmol/L SPEC 

Equivalent Amount of Perchlorate Ingestion Corresponding to the Excess SPEC 

The Clewell Perchlorate PBPK Model is used to calculate the external perchlorate 

exposure (mg/kg-day) from the excess SPEC observed in the exposed women (Clewell 2007). 

56
 
 

 

 

 

 

10-P-0101 

The excess SPEC of 4.90 μmol/L SPEC must be converted into μg/L SPEC unit for use in the 

Clewell Perchlorate PBPK Model. 

 μg/L SPEC(Exposed women) = 4.64 μmol/L SPEC x 99.45 μg perchlorate/μmol 

= 461 μg/L SPEC(Exposed women) or 0.461 mg/L SPEC(Exposed women) 

The external perchlorate dose required to generate the amount of excess NIS inhibition 

observed in the exposed workers is calculated using the Clewell PBPK model as follows: 

 Ext. ClO4

- Dose = 0.461 mg/L SPEC(Exposed women) x 1.0 mg/kg-day

 1.0 mg/L 

 = 0.461 mg/kg-day 

The exposed women in the Banerjee study were unable to maintain a normal T4 thyroid 

hormone level while still maintaining a TSH level in the normal range (refer to table above). 

The SPEC level at which overt hypothyroidism (i.e., elevated TSH and below normal T4) or 

subclinical hypothyroidism (i.e., elevated TSH and normal T4) is not known by experimental 

data. However, hypothyroxinemia is a less severe thyroid condition and is a common condition 

in pregnant women characterized by low maternal fT4 levels with normal TSH levels (Kooistra 

2006). Therefore, the exposed women’s thyroid condition could be described as 

hypothyroxinemia. Maternal hypothyroxinemia (i.e., during pregnancy) is documented to be 

associated with mental deficits (e.g., ADHD) in the children of those mothers (Vermiglio 2004). 

The mechanism of fetal brain damage from maternal hypothyroxinemia is the same as maternal 

hypothyroidism (i.e., an insufficient maternal supply of T4 to the fetus during gestation). 

Therefore, although hypothyroxinemia might not have overt adverse symptoms in adult women, 

maternal hypothyroxinemia is an adverse effect in the most sensitive populations – pregnant 

women, fetuses, and nursing infants. Thus, the OIG has identified the observed 

hypothyroxinemia in the Banerjee exposed women to be an adverse effect from which an excess 

NIS inhibition RfD can be calculated. 

The excess thiocyanate measured in the exposed women is converted by the use of the 

Tonacchera Model and the Clewell perchlorate PBPK model to calculate an external perchlorate 

dose that corresponds to the LOAEL of NIS inhibition in an adult male human. In other words, 

an external perchlorate exposure of 0.461 mg/kg-day (or 32 mg/day for a 70 kg adult female) 

should generate the same thyroid effects (i.e., hypothyroxinemia) observed in the exposed 

women in the Banerjee study. 

Calculation of an Excess NIS Inhibition RfD from the Excess Thiocyanate 

Exposure 

The severe hypothyroxinemia observed in the Banerjee exposed workers is used to 

identify the LOAEL for the calculation of the excess NIS inhibition RfD. Therefore, the 

observed LOAEL in an adult male is: 

LOAEL(Adult women) = 0.461 mg/kg-day 

57
 
 

10-P-0101 

The calculation of an NOAEL from a LOAEL is typically accomplished by applying a 

UF of 10 to the LOAEL (EPA 2002, p 4-44): 

NOAEL(Adult women) = 0.461 mg perchlorate equivalent/kg-day / 10 UF 

= 0.0461 mg perchlorate equivalent/kg-day 

Since the exposed women are expected to be more sensitive to NIS inhibition and 

because the use of hypothyroxinemia is a more subtle adverse thyroid effect than 

hypothyroidism, a scientific argument could be made to justify a smaller value of 10 for this UF 

(i.e., LOAEL to NOAEL). However, EPA risk assessment guidance states that a reduction of the 

intraspecies UF from a default of 10 is to be considered only if the POD is determined from the 

data obtained from the susceptible subpopulation (EPA 2002, p 4-43). Since nonpregnant 

women are not the sensitive population for this public health issue, this calculation of the excess 

NIS inhibition RfD(Women) from the excess exposure to thiocyanate in cow’s milk will use a UF of 

10. The application of a 10 UF in this calculation is analogous to the NAS Committee applying 

a total UF of 10 to the NOEL to protect the most sensitive population. From the excess 

perchlorate consumption in the Greer study, the NAS Committee used a NOEL and applied a UF 

of 10 to it to derive NAS-recommended perchlorate RfD (NAS 2005, p 16). The use of a UF of 

10 in our analysis also allows for the direct comparison of the excess NIS inhibition RfD from 

thiocyanate-perserved milk in adult women with the NAS-recommended perchlorate RfD of 

0.0007 mg/kg-day. Therefore, the excess NIS inhibition RfD(Women) is calculated as follows: 

Excess NIS Inhibition RfD(Adult women) = 0.0461 mg perchlorate equivalent/kg-day / 10 UF 

 = 0.0046 mg/kg-day 

The calculated excess NIS inhibition RfD from excess SCN- exposure in adult women is 

0.0046 mg/kg-day. EPA’s perchlorate RfD is 0.0007 mg/kg-day obtained from the NAS 

Committee. The calculated excess NIS inhibition RfD(Adult women) is 6.6 times greater than the 

NAS-recommended perchlorate RfD. 

The advantage of determining the excess NIS inhibition RfD is it used a conventional risk 

assessment approach of deriving an RfD by using a LOAEL observed in a human population. 

The NAS Committee describes its own approach of deriving an RfD from a NOEL as being an 

unconventional approach, but characterized it as being a “conservative, health-protective 

approach to the perchlorate risk assessment” (NAS 2005, p 15). The OIG’s conventional 

approach for deriving a perchlorate RfD independently supports the NAS Committee’s statement 

that its recommended perchlorate RfD is conservative. The excess NIS inhibition RfD(Adult 

women) observed in the Banerjee thiocyanate exposure study in milk indicates that the NASrecommended perchlorate RfD is conservative by a factor of 6.6. 

Discussion 

The following findings can be made from the observations in the two Banerjee 

thiocyanate exposure studies: 

58
 
10-P-0101 

•	 In both Banerjee thiocyanate exposure studies, the first observed adverse effect from 

excess exposure to NIS inhibition was hypothyroxinemia and not hypothyroidism as 

stated by the NAS Committee. 

•	 Both Banerjee thiocyanate exposure studies support the concept that the exposure to the 

other NIS inhibitors, thiocyanate and nitrate, have the same mechanism of toxicity as 

perchlorate, and an excess exposure on a molar potency adjusted basis is just as toxic as 

excess exposure to perchlorate. The toxic effects of the three NIS inhibitors are the same 

and the evaluation of the risk from three NIS inhibitors should not be separated, but 

should be considered together through a cumulative risk assessment approach. 

•	 Both Banerjee thiocyanate exposure studies support that the mathematical description of 

the Tonacchera Model for the TIU by the NIS. Hypothyroxinemia is known to be caused 

by iodide deficiency, which directly results in a low TIU. The Tonacchera Model 

predicts that a low TIU can also be generated when iodide intake is normal, but the total 

goitrogen load is excess. In both Banerjee thiocyanate exposure studies, the iodide intake 

was normal, but due to the excess exposure to NIS inhibitors, the same adverse effect 

observed with iodide deficiency is generated. This indicates that the lack of iodide acts 

as an NIS stressor producing the same effect to lower the uptake of iodide in the thyroid 

as does the exposure to NIS inhibitors. 

•	 The conventionally derived excess NIS inhibition RfD from excess SCN- exposure in 

adult males is calculated to be 0.0075 mg/kg-day. The NAS Committee’s recommended 

perchlorate RfD is 0.0007 mg/kg-day. The conventionally derived excess NIS inhibition 

RfD(Adult males) is 10.7 times greater than the NAS-recommended perchlorate RfD. The 

OIG’s conventional approach for deriving a perchlorate RfD independently supports the 

NAS Committee’s statement that its recommended perchlorate RfD is conservative. 

•	 The conventionally derived excess NIS inhibition RfD from excess SCN- exposure in 

adult women is 0.0046 mg/kg-day. The NAS Committee’s recommended perchlorate 

RfD is 0.0007 mg/kg-day. The conventionally derived excess NIS inhibition RfD(Adult 

women) is 6.6 times greater than the NAS recommended perchlorate RfD. The OIG’s 

conventional approach for deriving a perchlorate RfD independently supports the NAS 

Committee’s claim that its recommended perchlorate RfD is conservative. 

•	 Since both the excess NIS inhibition RfD and the NAS Committee’s recommended 

perchlorate RfD used a single chemical risk assessment approach to derive their 

respective RfD, both have the same limitations of a single chemical risk assessment. 

The pivotal perchlorate study by Greer used by NAS to derive the perchlorate RfD also 

does not identify or account for the varying amounts of NIS inhibition contributed by the other 

NIS inhibitors (i.e., nitrate or thiocyanate) among Greer’s test subjects. Furthermore, the Greer 

study does not identify the baseline amount of perchlorate from dietary exposure in the test 

subjects. Therefore, the perchlorate RfD derived from the Greer study is best described as the 

amount of excess NIS inhibition from perchlorate (i.e., the additional amount of perchlorate 

59
 
10-P-0101 

given to the Greer’s test subjects) that is not expected to reduce the amount of iodide uptake by 

the thyroid in sensitive human populations. Thus, the dataset used here from Banerjee’s 

thiocyanate study is no worse than Greer’s study from the perspective of not controlling for the 

nonmeasured NIS inhibitors. However, the Banerjee thiocyanate study does identify the baseline 

amount of thiocyanate in the controls. Both studies assume the background NIS inhibitor 

exposure levels from the nonmeasured NIS inhibitors are the same across the test subjects. 

Furthermore, neither the Greer study nor the male Banerjee thiocyanate study identified the 

iodide status of the test subjects, which is known to be a factor in the amount of iodide uptake by 

the NIS. Therefore, the amount of contributing inhibition from perchlorate and nitrate and the 

amount of iodide across the test subjects are potential confounding factors in the Greer and 

Banerjee studies. Obviously, a study in which all four variables (i.e., the amount of perchlorate, 

thiocyanate, nitrate, and iodide) are measured in the each of the test subjects would be ideal for 

applying and evaluating the Tonacchera Model, but this dataset is rare in the published literature. 

Our analysis found only one study (Braverman 2005) that measured all four NIS stressors in a 

single study population. This study is used to corroborate the calculated %TIU from the 

Tonacchera Model with the measured %TIU values from actual radioactive iodide uptake 

measurements reported in this human occupational cohort study (see Section 9.1.5). 

60
 
 

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5.1.4.3 Calculation of an Excess NIS Inhibition RfD Using the Adverse Effect 

Hypertrophy Observed in School-aged Children Drinking Nitrate-Contaminated 

Drinking Water 

Description of Tajtáková Nitrate Exposure Study 

The Tajtáková nitrate exposure study measured thyroid volume and echogenicity by 

ultrasound in 342 school-aged children from high-nitrate areas (HNAs) located in the agricultural 

lowland who consumed drinking water from shallow wells that were highly contaminated with 

nitrate (51-274 mg/L) in the Kosice Region of Slovakia (Tajtáková 2006). The study compared 

the HNA children’s thyroid volume and echogenicity results against 168 children of the same 

age from a low-nitrate area (LNA) who consumed low-nitrate drinking water (<2 mg/L). The 

HNA children’s results were also compared to 596 children from the City of Kosice who also 

consumed low-nitrate drinking water. The ages and genders of the children are as follows: 

Study Group 

Number of 

10-Year-Old Children 

Number of 

13-Year-Old Children 

324 Children from HNA 117 (49 boys / 68 girls) 207 (96 boys / 111 girls) 

168 Children from LNA 65 (24 boys / 41 girls) 103 (60 boys / 43 girls) 

596 Children from Košice City 

(also a low-nitrate area) 171 (68 boys / 103 girls) 425 (163 boys / 262 girls) 

HNA = high-nitrate area; LNA = low-nitrate area. 

Source: Tajtáková 2006. 

Blood samples were taking from 315 HNA children and 109 LNA children (no blood 

samples were taken from the Košice City children). The blood was analyzed for levels of TSH, 

total thyroxine (tT4), free triiodothyronine (fT3), and thyroperoxidase antibodies (anti-TPO) in 

the serum. 

Iodide Nutritional Status 

The urinary iodine concentration in the HNA group (n=53) had a mean ± SD of 154 ± 

108 μg/L, median 150 μg/L, range 24-320 μg/L, and 79% of the urinary concentrations were > 

100 μg/L. The urinary iodine concentration in the LNA group (n=32) had a mean ± SD of 125 ± 

48 μg/L, median 126 μg/L, range 60-173 μg/L, and 64% of the urinary concentrations were > 

100 μg/L. The recommend urinary iodine concentration for adolescents and children (6-12 yrs) 

is 100 to 200 μg/L (Delange 2005, p 278). Therefore, the urinary iodine concentration in both 

HNA and LNA groups indicate satisfactory and healthy iodide intake amounts. 

Tajtáková Nitrate Exposure Study Results 

In regard to the thyroid volume, both the 10-year-old and 13-year-old HNA children had 

statistically significant increases in the size of their thyroid (i.e., hypertrophy) as compared to the 

LNA children and the children from Košice City. The observed thyroid volume in the 10 year 

olds increased from 4.58 mls in the LNA children to 5.10 mls in the HNA children (i.e., a 11% 

increase). Furthermore, the observed thyroid volume in the 13 year olds increased from 5.23 mls 

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in the LNA children to 5.97 mls in the HNA children (i.e., a 14% increase). The thyroid volume 

results are summarized in the following table: 

Study Groups 

Thyroid Volume 

10-year-old Children 13-year-old Children 

324 Children from HNA 5.10 ± 0.14 ml 5.97 ± 0.11 ml 

168 Children from LNA 4.58 ± 0.17 ml (p <0.02) 5.23 ± 0.15 ml (p < 0.05) 

596 Children from Košice City 

(also a low-nitrate area) 4.77 ± 0.10 ml (p <0.05) 4.87 ± 0.14 ml (p < 0.0001) 

HNA = high-nitrate area; LNA = low-nitrate area. 

Source: Tajtáková 2006. 

In regard to the frequency of hypoechogenicity, both the 10-year-old and 13-year-old 

HNA children had statistically higher frequencies of hypoechogenicity as compared to the LNA 

children plus the children from Košice City. The frequency of hypoechogenicity is summarized 

in the following table: 

Study Groups 

Frequency of Hypoechogenicity 

10-year-old Children 13-year-old Children 

Children from HNA 16/177 (13.7%) p<0.01 22/207 (10.6%) p<0.03 

Children from LNA & Košice City 11/236 (4.7%) 30/528 (5.7%) 

Source: Tajtáková 2006. 

In regard to TSH levels, of the 315 HNA children tested for TSH, 13 were found to be in 

the TSH hypothyroid range (i.e., >4.0mU/l). By contrast, of the 109 LNA children tested for 

TSH, none were found to be in the TSH hypothyroid range. 

In regard to anti-TPO values, of the 315 HNA children tested for anti-TPO, 8 were found 

to be anti-TPO positive. By contrast, of the 109 LNA children tested for anti-TPO, none were 

found to be anti-TPO positive. 

In regard to the blood sample results, the measured tT4 and fT3 levels between the HNA 

and LNA schoolchildren were found to have no statistical difference. The blood sample results 

for tT4 and fT3 are provided in the following table: 

Study Groups 

Blood Sample Results 

Total Thyroxine (tT4) Free Triiodothyronine (fT3) 

315 Children from HNA 

(10- & 13-year-old pooled results) 88.9 ± 26.9 nmol/L 5.9 ± 1.0 pmol/L 

109 Children from LNA 

(10- & 13-year-old pooled results) 82.1 ± 22.6 nmol/L 6.0 ± 0.9 pmol/L 

Source: Tajtáková 2006 

Estimated Excess Nitrate Exposure from Drinking Water in HLA Children 

The total number of nitrate-contaminated wells in the study is 45. The total weighted 

nitrate concentration is 6878 well-mg/L. Therefore, the estimated nitrate concentration in the 

HLA is 152.8 mg/L (i.e., 6878 well-mg/L divided by 45 wells). Since the LNA children and the 

Košice children drank water containing up to <2 mg/L nitrate, the amount of excess nitrate 

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concentration in the HNA children’s drinking water ingestion is estimated to be 150.8 mg/L (i.e., 

152.8 mg/L – 2.0 mg/L). 

Number of 

Contaminated 

Wells 

Nitrate Concentration Range 

Reported in the Wells 

(mg/L) 

Mid-Range Nitrate 

Concentration 

(mg/L) 

Weighted Nitrate 

Concentration 

(well-mg/L) 

14 214-264 239 3346 

16 101-200 150 2400 

15 51-100 75.5 1132 

Total = 45 Total = 6878 

Source: OIG Analysis. 

The amount of excess nitrate exposure per day in the HNA children is estimated to be 

150.8 mg/day (i.e., 150.8 mg of excess nitrate/L x 1 liter/person/day). This is calculated from the 

amount of excess nitrate concentration in the HNA children’s drinking water multiplied by the 

median drinking water consumption rate of 1 liter/person/day. Since the water consumption rate 

of children in Slovakia is undocumented, the mean daily average ingestion of community water 

of 1.0 L/person/day for a consumer in the U.S. population was taken from EPA guidance (EPA 

2004, p 4-2). The drinking water consumption rate of Slovakian children may be higher or 

lower. 

Amount of Excess NIS Inhibition from Excess Nitrate in the School-Aged Children 

The amount of excess NIS inhibition from excess nitrate in school-aged children is 

measured by the following ingested-weight basis using the OPEC equation (concept adapted 

from Tonacchera 2004; De Groef 2006, p 155): 

OPEC = (Amt of ClO4

-

 Inhibition) + (Amt of NO3

-

 Inhibition) + (Amt of SCN- Inhibition) 

 = grams of ClO4

-

 + grams of NO3

- /150 + 0.5 free SCN-

 x grams of SCN- /8.8 

Where: 

Oral inhibition potency of perchlorate = 1 

Oral inhibition potency of nitrate relative to perchlorate = 1 / 150 

Oral inhibition potency of thiocyanate relative to perchlorate = 1 / 8.8 

Therefore, the amount of Excess NO3

- Inhibition is: 

 Excess OPEC(Children) = grams excess Nitrate ÷ 150 

 = 150.8 mg/day ÷ 150 

 = 1.005 mg of perchlorate equivalent/day 

Calculation of an Excess NIS Inhibition RfD form the Excess Nitrate Exposure 

The thyroid hypertrophy observed in the HNA school-aged children is used to identify 

the NOAEL for the calculation of the excess NIS inhibition RfD. In a study of 143 Nigerian 

adults, the mean thyroid volume was reported to be 9.55 mls ± 1.82 (Ahidjo 2006). This value is 

consistent with the thyroid volume range of 8 -12 mls for females and 11 -15 mls for males in 

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Iceland, Sweden, the Netherlands, and the United States (Langer 1989). Therefore, the thyroid 

volume in an adult has to approximately double before being considered abnormal. The 

recommended upper limit for thyroid volume in an adult population is 18 mls (Ivanac 2004). 

The observed thyroid volume in the 10-year-olds increased from 4.58 mls in the LNA children to 

5.10 mls in the HNA children (i.e., an 11% increase). Furthermore, the observed thyroid volume 

in the 13-year-olds increased from 5.23 mls in the LNA children to 5.97 mls in the HNA children 

(i.e., a 14% increase). The recommended upper limit for thyroid volume in children under 15 

years old is 16 mls (Ivanac 2004). Although a statistically significant increase in thyroid volume 

was observed between the LNA and HNA children in the Tajtáková study from the increase 

exposure to nitrate in the drinking water, the increase in thyroid volume was not large enough to 

be considered a LOAEL. 

No statistical difference was found in tT4 and fT3 thyroid hormone levels between the 

HNA and LNA schoolchildren. Since a decreased supply of fT4 during pregnancy is the 

proposed mechanism leading to fetal brain damage, the lack of a decrease in the supply of T4 

suggests the observed thyroid volume effect is probably occurring below the NOAEL. 

Therefore, the excess NIS Inhibition RfD(children) calculated below is probably greater, hence the 

use of the greater-than symbol (≥). 

A NOAEL is expressed on a daily dose-per-kg basis (i.e., mg/kg-day). Therefore, the 

average weight of the HNA school-aged children is needed, but this data point is not provided in 

the study. Therefore, the average weight of the HNA school-aged children needs to be 

estimated. The following table provides weight data on 10- and 13-year-old children to estimate 

an average weight for the test population: 

Gender 

10-Year-Old HNA Children 13-Year-Old HNA Children 

Number in 

HNA Group 

Median 

Weight (kg) 

Combined 

Weight (kg) 

Number in 

HNA Group 

Median 

Weight (kg) 

Combined 

Weight (kg) 

Boys 49 31 1519 96 50 4800 

Girls 68 29 1972 111 49 5439 

Totals 117 3491 207 10239 

Source of weight data: EPA 2004, table 7.2. 

Therefore, the estimated median weight of the 324 HNA school-aged children is 42.4 kg 

(i.e., (10239 kg + 3491 kg)/(117 + 207 children)). Therefore, the calculated NOAEL for the 

median 42.4 kg HNA school-aged child is: 

NOAEL ≥ 1.005 mg perchlorate equivalent/day /42.4 kg 

≥ 0.0237 mg perchlorate equivalent/kg-day 

The NAS Committee applied a total UF of 10 (i.e., an intraspecies factor) to the NOEL to 

protect the most sensitive population – the fetuses of pregnant women who might have 

hypothyroidism or iodide deficiency (NAS 2005, p 16). Although 10- and 13-year-old schoolaged children are expected to be more sensitive to NIS inhibition than an adult, an intraspecies 

UF smaller than 10 could be proposed. However, EPA risk assessment guidance states that a 

reduction of the intraspecies UF from a default of 10 is to be considered only if the POD is 

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determined from the data obtained from the susceptible subpopulation (EPA 2002, p 4-43). 

Since children are not the sensitive population for this public health issue, this calculation of the 

excess NIS inhibition RfD(Children) from the excess exposure to nitrate in school-aged children 

uses a UF of 10 as follows: 

Excess NIS Inhibition RfD(Children) ≥ 0.0237 mg perchlorate eq./kg-day / 10 UF 

≥ 0.0024 mg perchlorate eq ./kg-day 

The calculated excess NIS inhibition RfD from excess nitrate exposure in school-aged 

children is greater than 0.0024 mg/kg-day. EPA’s perchlorate RfD is 0.0007 mg/kg-day, 

obtained from the NAS Committee. The calculated excess NIS inhibition RfD(children) is at least 

3.4 times greater than the NAS-recommended perchlorate RfD. 

Determining the excess NIS inhibition RfD is an advantage because it used a 

conventional risk assessment approach of deriving an RfD by using a NOAEL observed in a 

human population. The NAS Committee describes its own approach of deriving an RfD from a 

NOEL as being an unconventional approach, but characterized it as being a “conservative, 

health-protective approach to the perchlorate risk assessment” (NAS 2005, p 15). The OIG’s 

conventional approach for deriving a perchlorate RfD independently supports the NAS 

Committee’s statement that its recommended perchlorate RfD is conservative. The excess NIS 

inhibition RfD(Children) observed in the Tajtáková nitrate exposure study indicates that the NASrecommended perchlorate RfD is conservative by a factor of at least 3.4. 

Discussion 

The following findings can be made from the observations in the Tajtáková nitrate 

exposure study: 

•	 The Tajtáková exposure study supports the concept that the exposure to the other NIS 

inhibitors, thiocyanate and nitrate, have the same mechanism of toxicity as perchlorate 

and an excess exposure on a molar potency adjusted basis is just as toxic as excess 

exposure to perchlorate. The toxic effects of the three NIS inhibitors are the same and 

the evaluation of the risk from three NIS inhibitors should not be separated, but should be 

considered together through a cumulative risk assessment approach. 

•	 The conventionally derived excess NIS inhibition RfD from excess nitrate exposure in 

school-aged children is calculated to be 0.0024 mg/kg-day mg/kg-day. The NAS 

Committee’s recommended perchlorate RfD is 0.0007 mg/kg-day. The conventionally 

derived excess NIS inhibition RfD(Adult males) is > 3.4 times greater than the NASrecommended perchlorate RfD. The OIG’s conventional approach for deriving a 

perchlorate RfD independently supports the NAS Committee’s claim that its 

recommended perchlorate RfD is conservative. 

•	 Since both the excess NIS inhibition RfD and the NAS Committee’s recommended 

perchlorate RfD used a single chemical risk assessment approach to derive their 

respective RfD, both have the same limitations of a single chemical risk assessment. 

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6. Application of the Tonacchera Model to the Chilean Epidemiological Studies 

This section discusses the application of the Tonacchera Model to the two 

epidemiological studies conducted on the perchlorate exposed populations of northern Chile. 

6.1 Tellez Study 

Dr. Rafael Tellez of the Medicine Service in Puente Alto, Chile, led a longitudinal 

epidemiological study in northern Chile to evaluate the impact of perchlorate exposure to 

drinking water of 113.9 μg/L on the maternal thyroid during pregnancy, neonatal thyroid 

function, the developmental status at birth, breast milk iodide, and perchlorate levels during 

lactation (Tellez 2005). The Tellez study was conducted in the same three coastal cities in 

northern Chile (i.e., Antofagasta, Chanaral, and Taltal) as the Crump study that evaluated the 

impact of perchlorate exposure on school-aged children and newborns (Crump 2000). Since 

only preliminary results from the Tellez study were available to the NAS Committee, the Tellez 

study was not used in the formulation of the NAS Committee’s conclusions (NAS 2005, p 106). 

The Tellez study accounted for both drinking water and dietary exposure to perchlorate. 

The pregnant mothers from Taltal were found to have perchlorate exposure at about 118.8 

μg/day or 2.42 times the EPA RfD. The following table summarizes the perchlorate exposure in 

the pregnant mothers and neonates in the three northern Chilean cities: 

Perchlorate Exposure in Chilean Pregnancy and Neonate Study 

Perchlorate Exposure Groups 

Parameter Antofagasta Chanaral Taltal 

Mean Perchlorate in Tap 

Water 

0.5 μg/L 

< 4.0 μg/L (all samples) 5.82 ± 0.63 μg/L 113.9 ± 13.3 μg/L 

Est. Drinking Water 

Perchlorate Exposure 0.42 μg/day 6.1 μg/day 93.5 μg/day 

Est. Dietary Perchlorate 

Exposure 21.7 μg/day 33.8 μg/day 25.3 μg/day 

Est. Median Daily 

Perchlorate Exposure 

(i.e., urinary excretion) 22.1 μg/day 40.0 μg/day 118.8 μg/day 

Perchlorate Exposure 

Fraction of EPA RfD 

of 49 μg/day 0.45 RfD 0.82 RfD 2.42 RfD 

Source: Tellez 2005. 

The concept of external dose is a crude technique to measure human exposure. As seen 

in Clewell’s perchlorate PBPK model, an external dose of 1 μg/kg-day generates different 

internal serum concentrations (i.e., internal indices) in each of the following life stages: fetus, 

neonate, child, adult, pregnant women, and lactating women (Clewell 2007, table 4). The use of 

an internal indice is critical because the biological impact is directly related to the concentration 

of perchlorate in direct contact with the NIS (i.e., bathing the symporter). Therefore, internal 

indices of perchlorate serum concentration are a better measure of exposure than the external 

perchlorate dose. The same external dose can result in significantly different internal indices. 

For example, an external dose of 1 μg/kg-day (i.e., 70 μg/day for an adult) would predict an 

adult’s perchlorate serum concentration to be 2 μg/L. However, the same external dose of 

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1 μg/kg-day in a pregnant mother is predicted to have a 5 μg/L perchlorate serum concentration. 

Although both the adult and pregnant mother have the same external dose, the pregnant mother 

has 2.5 times the perchlorate serum concentration in direct contact with the NIS. This means the 

pregnant mother has 2.5 times the amount of NIS inhibition more than the adult for the same 

external dose. This is important because the perchlorate RfD is expressed as an external dose, 

not an internal indice. 

The strategy of the 2007 NAS Toxicity Testing Committee was to define the critical 

internal tissue concentration (i.e., internal indices) that perturbs the biological pathway and then 

use pharmacokinetic modeling to determine what external dose generates the critical internal 

dose (NAS 2007, prepub. summary p 5). To apply the NAS Toxicity Testing Committee’s 

approach to the perchlorate RfD, the internal perchlorate serum concentration must be 

determined at the external RfD dose of 0.7 μg/kg-day. The Clewell Perchlorate PBPK Model 

predicts a perchlorate serum of 2 μg/L for an adult at an external dose of 70 μg/day (i.e., 

1 μg/kg-day or 1.42 times the RfD). If this value is linearly scaled down to the EPA RfD of 

49 μg/day in an adult (i.e., 0.7 μg/kg-day), the predicted perchlorate serum concentrations at 

EPA’s RfD in an adult would be 1.4 μg/L. However, the EPA RfD was derived by applying a 

10-fold UF to the NOEL of 7 μg/kg-day observed in Greer’s subjects (NAS 2005, p 15). 

Therefore, the perchlorate NOEL corresponds to an external dose of 490 μg/day. The closest 

point provided in Clewell’s paper is that an external dose of 700 μg/day is predicted to generate a 

perchlorate serum concentration of 10 μg/L in an adult (Clewell 2007, table 4). If this value is 

linearly scaled down to the perchlorate NOEL of 490 μg/day in an adult (i.e., 7 μg/kg-day), the 

predicted perchlorate serum concentrations at the NOEL in an adult would be about 7 μg/L. 

Therefore, any perchlorate serum concentrations above 7 μg/L would be expected to generate 

observed effects (i.e., changes in the thyroid hormones and TSH levels). 

The following table provides a summary of the internal indices exposures in the pregnant 

mothers and neonates in the Tellez study: 

Serum Perchlorate Exposures in Tellez Study 

Parameter 

Perchlorate Exposure Groups 

Antofagasta Chanaral Taltal 

Mothers’ Perchlorate Serum 

at ~16 Weeks of Gestation 

< 4 μg/L 

(n = 3) 

< 4 μg/L 

(n = 7) 

10.9 ± 2.1 μg/L 

(n = 14) 

Mothers’ Perchlorate Serum 

at ~32 Weeks of Gestation 

< 4 μg/L 

(n = 5) 

< 4 μg/L 

(n = 5) 

13.2 ± 1.7 μg/L 

(n = 6) 

Neonates’ Perchlorate Serum 

at Birth (i.e., newborns) < 4 μg/L < 4 μg/L 

19.9 ± 5.0 μg/L 

(n = 14) 

Source: Tellez 2005. 

The observed perchlorate serum concentration in the pregnant Taltal mothers is 10.9 μg/L 

at ~ 16 weeks of gestation and 13.2 μg/L at ~32 weeks of gestation. This agrees with the 

predicted perchlorate concentration estimated by the Clewell PBPK model for pregnant women. 

An external dose of 70 μg/day is predicted by the model to generate a perchlorate serum 

concentration of 5 μg/L (Clewell 2007, table 4). A simple linear scaling up of the model’s 

pregnant mothers’ perchlorate serum concentration by a factor of 1.7 (i.e., 118.8 μg/day ÷ 

70μg/day – because of the daily perchlorate exposure in Taltal of 118.8μg/day) gives a predicted 

serum concentration for the pregnant Taltal mothers of 8.5 μg/L. 

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In the Tellez study, the pregnant Taltal mothers had perchlorate serum concentrations of 

10.9 μg/L and 13.2 μg/L. The Taltal neonates had an even higher perchlorate serum 

concentrations of 19.9 μg/L. All of these values are above the perchlorate NOEL observed in 

Greer’s test subjects. Any perchlorate serum concentrations above 7 μg/L would be expected to 

generate observed effects (i.e., changes in the thyroid hormones and TSH). However, both the 

pregnant Taltal mothers and the Taltal newborns had normal health function thyroid performance 

(Tellez 2005, table 3). 

As an indicator of thyroid stress, the differences in the TSH levels in the pregnant 

mothers across the three cities was not statistically significant. However, at each testing interval, 

the highest perchlorate exposure group (Taltal) always had the lowest TSH level. The T3, free 

T4, and TSH results listed in Table 3 of Tellez’s paper for all three testing intervals indicate that 

the thyroids in the Taltal pregnant mothers are normal, healthy, and not challenged by the 

relatively large perchlorate exposure (Tellez 2005). The following table summaries the TSH 

levels in the pregnant mothers: 

TSH levels in Pregnant Mothers in the Tellez Study 

Perchlorate Exposure Groups Statistical 

Parameter Antofagasta Chanaral Taltal Significance

TSH level (μU/ml) 

at ~16 Weeks of Gestation 2.63 2.81 2.61 0.91 

TSH level (μU/ml) 

at ~32 Weeks of Gestation 3.69 2.55 2.08 0.63 

TSH level (μU/ml) 

Postpartum 8.25 2.34 1.95 0.79 

Source: Tellez 2005, table 3. 

The differences in the free T4 and TSH levels in the neonates across the three cities were 

not statistically significant. The T3 level in Chanaral was statistically significantly lower than the 

other two cities. These data indicate that the thyroids in the Taltal neonates are normal, healthy, 

and not challenged by the relatively large perchlorate exposure. The following table summarizes 

the thyroid hormones, TSH, and serum perchlorate levels in neonates across the three cities: 

Thyroid Hormones and TSH levels in Neonates in the Tellez Study 

Perchlorate Exposure Groups Statistical 

Parameter Antofagasta Chanaral Taltal Significance

T3 (ng/dL) 79 ± 13.4 73 ± 17.9 82 ± 20.6 0.03 

Free T4 (ng/dL) 1.07 ± 0.16 1.04 ± 0.13 1.03 ± 0.14 0.73 

TSH Level (μU/ml) 6.20 ± 2.96 6.69 ± 4.13 6.31 ± 2.91 0.99 

Serum Perchlorate (μg/L) < 4 < 4 19.9 ± 5.0 0.005 

Source: Tellez 2005, table 4. 

Given that the perchlorate NOEL determined in the Greer test subjects had an internal 

indice of 7 μg/L, the pregnant mothers and newborns in Taltal had serum perchlorate levels well 

above the NOEL. On an internal indices basis, the Taltal pregnant mothers were about 1.6 and 

1.9 times the NOEL at ~16 and ~32 weeks of gestation, respectively. Furthermore, the Taltal 

neonates were about 2.8 times above the NOEL. Application of the Greer NOEL requires the 

Tellez study to have detected changes in the thyroid hormones and TSH levels in both the Taltal 

68
 
 

 

 

 

10-P-0101 

pregnant mothers and neonates. This is a striking contradiction between the Greer study and the 

Tellez study that must be explained. It is simply not logical that the Taltal pregnant women and 

neonates are less sensitive to perchlorate inhibition then the adults in the Greer study. This 

contradiction between the Greer study and the Tellez study requires evaluating and considering 

potential confounding variable(s) at work to account for this discrepancy. 

The Tonacchera Model identifies and simultaneously quantifies the amount of interaction 

between the following four variables affecting the uptake of iodide into the thyroid by the NIS: 

iodide, perchlorate, nitrate, and thiocyanate. The Tonacchera Model evaluates the total NIS 

inhibition load (i.e., total goitrogen load) acting on the body. The Tellez study does not provide 

nitrate exposure data in the pregnant mothers, but the study did measure perchlorate serum 

concentrations at ~16 and ~32 weeks of gestation and thiocyanate serum concentrations at 

postpartum. The following table summarizes the known NIS inhibitor exposures in the pregnant 

mothers (note that the NIS inhibitors are also provided in μmol/L to facilitate their use in 

determining the total goitrogen load acting on the pregnant mothers): 

NIS Inhibitor Exposures in Pregnant Mothers in Tellez Study 

Parameter 

Perchlorate Exposure Groups 

Antofagasta Chanaral Taltal 

Perchlorate Serum 

at ~ 6 Weeks of Gestation 

< 4 μg/L 

(n = 3) 

< 0.04 μmol/L 

< 4 μg/L 

(n = 7) 

< 0.04 μmol/L 

10.9 ± 2.1 μg/L 

(n = 14) 

0.11 μmol/L 

Perchlorate Serum 

at ~32 Weeks of Gestation 

< 4 μg/L 

(n = 5) 

< 0.04 μmol/L 

< 4 μg/L 

(n = 5) 

< 0.04 μmol/L 

13.2 ± 1.7 μg/L 

(n = 6) 

0.13 μmol/L 

Thiocyanate Serum 

Postpartum 

20.0 ± 10.9 μmol/L 

(n = 9) 

17.4 ± 16.1 μmol/L 

(n = 21) 

12.6 ± 6.4 μmol/L (n = 

10) 

Source: Tellez 2005. 

The total NIS inhibition load (i.e., total goitrogen load) acting on the body is determined 

by calculating the SPEC as follows (concept taken from Tonacchera 2004): 

SPEC = (Amt of ClO4

-

 Inhibition) + (Amt of NO3

-

 Inhibition) + (Amt of free SCNInhibition) 

SPEC = [ClO4

-

] + [NO3

-

] /240 + [free SCN-] /15 

Where: [ ] is molarity 

Serum inhibition potency of perchlorate = 1 

Serum inhibition potency of nitrate relative to perchlorate = 1 / 240 

Serum inhibition potency of thiocyanate relative to perchlorate = 1 / 15 

[free SCN-

] = [total serum SCN-] x 0.5 free SCN- /total serum SCNUsing the measured perchlorate serum at ~32 weeks of gestation and thiocyanate serum 

concentrations at postpartum, the total NIS inhibitor load can be estimated in the pregnant 

mothers from each of the three cites. However, the Tellez study did not measure the nitrate 

exposure, and as another NIS inhibitor, nitrate could serve as an uncontrolled confounding 

variable. However, the amount of NIS inhibition typically contributed from nitrate is only about 

11% (i.e., nitrate SPEC of 0.167 μmol/L out of a total SPEC for the adult of 1.501 μmol/L) of 

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the body’s total goitrogen load. In the Western world, the typical nitrate serum concentration 

ranges from 10-140 μmol/L with the mean nitrate serum concentration being 30-50 μmol/L 

(Tonacchera 2004). Therefore, an estimated nitrate exposure of 40 μmol/L will be used for all 

three cities in this calculation of the pregnant mothers’ total NIS inhibition load (i.e., since each 

value is the same, this will not change the relative ranking of total goitrogen loads between the 

cities). The nitrate exposure in Taltal would have to increase by at least a factor of 2 (i.e., to 80 

μmol/L) over nitrate exposure in Antofagasta and Chanaral to cause Taltal to have the largest 

total goitrogen load. The following are calculations for the total NIS inhibition in the pregnant 

mothers in each of the three cities from the Tellez study (expressed as SPECs): 

Antofagasta SPEC = 0.04 μmol/L + (40.0 μmol/L ÷ 240) + (20.0 μmol/L x 0.5 free SCN- ÷ 15) 

= 0.04 μmol/L + 0.17 μmol/L + 0.67 μmol/L 

 = 0.88 μmol/L 

Chanaral SPEC = 0.04 μmol/L + (40.0 μmol/L ÷ 240) + (17.4 μmol/L x 0.5 free SCN-

 ÷ 15) 

= 0.04 μmol/L + 0.17 μmol/L + 0.58 μmol/L 

 = 0.79 μmol/L 

Taltal SPEC = 0.13 μmol/L + (40.0 μmol/L ÷ 240) + (12.6 μmol/L x 0.5 free SCN-

 ÷ 15) 

= 0.13 μmol/L + 0.17 μmol/L + 0.42 μmol/L 

 = 0.72 μmol/L 

The total NIS inhibition load (i.e., total goitrogen load) acting on the neonate can also be 

determined by calculating the SPEC. The Tellez study did not measure thiocyanate 

concentrations in neonates. However, the OIG identified four papers that document the transfer 

of thiocyanate from the mother’s blood to the neonate’s blood through the placenta (Hauth 1984; 

Laurberg 2004; Nafstad 1995; Vanderpas 1984). We provided this information above in a table 

under the section Total NIS Inhibitor Exposure in Fetuses. These four papers clearly report 

thiocyanate serum concentration ratios of the cord serum to the mother’s serum in the range of 

68-111%. The observed thiocyanate concentrations in the pregnant mother at the postpartum 

examination was 20.0 μmol, 17.4 μmol, and 12.6 μmol for Antofagasta, Chanaral, and Taltal, 

respectively. 

The closest match in the data from the four papers is in Hauth’s study. The Hauth study 

reported a thiocyanate serum concentration of 32.2 μmol and 23 μmol in the mother’s serum and 

the neonate’s serum, respectively. In the Hauth study, the observed thiocyanate serum 

concentration ratio of the cord serum to the mother’s serum in nonsmokers was 71%. The 

amount of thiocyanate transfer from the mother to the neonate will be used to estimate the 

expected thiocyanate concentrations in the neonates in the Tellez study. The amount of nitrate in 

the neonate’s serum is not reported in the Tellez study. Therefore, nitrate is unknown and 

represents a potential confounding variable. However, the amount of NIS inhibition typically 

contributed by nitrate in an adult is only about 11% (i.e., nitrate SPEC of 0.167 μmol/L out of a 

total SPEC for the adult of 1.501 μmol/L) of the body’s total goitrogen load. Furthermore, if the 

nitrate exposure is the same across the three cities, the relative ranking of total NIS inhibition 

load would not change. The following table summarizes the neonate exposure to NIS inhibitors 

(note that the NIS inhibitors are also provided in μmol/L to facilitate their use in determining the 

total goitrogen load acting on the neonates): 

70
 
 

 

 

 

 

 

 

10-P-0101 

NIS Inhibitor Exposures in Neonates in Tellez Study 

Exposure Groups 

Parameter Antofagasta Chanaral Taltal 

Perchlorate Serum in 

Neonates at Birth 

< 4 μg/L 

(n = 4) 

< 0.04 μmol/L 

< 4 μg/L 

(n = 1) 

< 0.04 μmol/L 

19.9 ± 5.0 μg/L 

(n = 14) 

0.20 μmol/L 

Thiocyanate Serum in 

Pregnant Mother at 

Postpartum 

20.0 ± 10.9 μmol/L 

(n = 9) 

17.4 ± 16.1 μmol/L 

(n = 21) 

12.6 ± 6.4 μmol/L (n = 

10) 

Estimated Neonate 

Thiocyanate Serum Using a 

70% Equilibrium 14.2 μmol/L 12.4 μmol/L 8.9 μmol/L 

Source: Tellez 2005. 

The following are calculations for the total NIS inhibition in neonates in each of the three 

cities in the Tellez study (expressed as SPECs): 

Antofagasta SPEC = 0.04 μmol/L + (nitrate ? μmol/L ÷ 240) + (14.2 μmol/L x 0.5 free SCN- ÷ 15) 

= 0.04 μmol/L + unknown nitrate amount + 0.47 μmol/L 

 = 0.51 μmol/L 

Chanaral SPEC = 0.04 μmol/L + (nitrate ? μmol/L ÷ 240) + (12.4 μmol/L x 0.5 free SCN- ÷ 15) 

= 0.04 μmol/L + unknown nitrate amount + 0.41 μmol/L 

 = 0.45 μmol/L 

Taltal SPEC = 0.13 μmol/L + (nitrate ? μmol/L ÷ 240) + (8.9 μmol/L x 0.5 free SCN-

 ÷ 15) 

= 0.20 μmol/L + unknown nitrate amount + 0.30 μmol/L 

 = 0.50 μmol/L 

The Tellez epidemiological study was designed to compare the thyroid health effects in 

the high perchlorate exposure city of Taltal against two cities, Antofagasta and Chanaral, which 

have much lower perchlorate exposure. The authors concluded that “ . . . the perchlorate dose in 

Taltal was not sufficiently high to stress the maternal or neonatal thyroid.” However, nitrate and 

thiocyanate are also known NIS inhibitors and act as potential confounding variables. Since 

thiocyanate levels were measured in the Tellez study, this analysis shows that the level of 

thiocyanate exposure in both the pregnant mothers and neonates causes a much greater amount 

of NIS inhibition than even the amount of NIS inhibition from consuming 118 ppb of perchlorate 

in the tap water. The relatively low thiocyanate exposure in Taltal causes the Taltal group to 

actually have the least amount of total NIS inhibition and the least “stressed” or challenged 

thyroids in the group (i.e., excluding the impact of iodide, to be discussed later). In other words, 

when considered from a total goitrogen load, the experimental design of this epidemiological 

study is flipped: Taltal is the control group (i.e., no longer the exposed group), and Antofagasta 

is the exposed group (i.e., no longer the control group). Actually, since there is only a relatively 

small difference in the Total NIS Inhibitor Load in the pregnant mothers between Taltal and 

Antofagasta, the study becomes the equivalent of comparing three control groups together. From 

the view point of total NIS inhibition load, there is no surprise then that the data show little 

difference in the thyroid health between the three cities. The following table summarized the 

relative total NIS inhibition load in the Tellez study: 

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Relative Total NIS Inhibition Load in the Tellez Study 

Cities 

Parameter Antofagasta Chanaral Taltal 

Mean Perchlorate in Tap Water 0.5 μg/L 5.82 μg/L 113.9 μg/L 

Estimated Total Perchlorate Exposure 22.1 μg/day 40.0 μg/day 118.8 μg/day 

Relative Perchlorate Exposure Low medium high 

Estimated Total NIS Inhibition Load 

in Pregnant Mothers 0.88 μmol/L 0.79 μmol/L 0.72 μmol/L 

Est. NIS Inhibition Load in Neonate 

(excluding nitrate due to a lack of data) 0.51 μmol/L 0.45 μmol/L 0.50 μmol/L 

Total NIS Inhibition Load Observed in 

Pregnant Mothers 

(i.e., total goitrogen load) 

Highest 

(becomes the 

experimental group) In the middle 

Lowest 

(becomes the 

control group) 

Difference in Total NIS Inhibition Load 

Observed in Neonates 

(i.e., total goitrogen load) 

Not much 

difference 

Not much 

difference 

Not much 

difference 

Source: OIG Analysis; summary of Tellez study results. 

The Tellez study can be related back to the conditions in the United States using the 

Tonacchera Model. In the United States, the typical total NIS inhibition load is 1.500 μmol/L 

(which, calculated previously in this document, assumes a median serum concentration of 

40μmol/L for both nitrate and thiocyanate). In the Tellez study in Chile, the pregnant mothers’ 

total NIS inhibition load was 0.88 μmol/L, 0.79 μmol/L, and 0.72 μmol/L in Antofagasta, 

Chanaral, and Taltal, respectively. Therefore, the typical U.S. adult has a total NIS inhibition 

load that is 170%, 190%, and 208% greater than those in Antofagasta, Chanaral, and Taltal, 

respectively. Furthermore, the median UIC is 140 μg/L in U.S. pregnant women (NAP 2000). 

In the Tellez study, the entire Chilean study group had a reported median UIC of 269 μg/L which 

is 92% greater than the United States. The recommended UIC for pregnant and lactating women 

is reported at 200-300 μg/L (Delange 2005, p 278, table 11E.8). The median UIC indicating 

optimal iodide nutrition during pregnancy and lactating women could be in the range of 150-230 

μg/L (Delange 2004). 

The difference in TIU between pregnant women in the United States and Chile can be 

calculated using the Tonacchera Model TIU is calculated by using the following equation: 

TIU = constant x [I-

] / (1.22 + [SPEC]) 

where: SPEC = [ClO4

-

] + [NO3

-

] /240 + [free SCN- ] /15 

Note: The Tonacchera Model uses concentration expressed in units of μmol/L. 

 Restated: 

TIU is proportional to [I-

] / (1.22 + [SPEC]) 

Estimated TIU in U.S. Pregnant Women 

The TIU in the U.S. pregnant women is determined by substituting values into the 

Tonacchera Model. The [I-

] in the serum is unknown but is directly related to the UIC. The [I-] 

is assigned a value of “x”. In the United States, the typical total NIS inhibition load is 1.501 

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μmol/L (which, calculated previously in this document, assumes a median serum concentration 

of 40μmol/L for both nitrate and thiocyanate). 

Therefore, the TIU in the U.S. pregnant women is expressed by: 

 TIU (U.S. pregnant women) || [I-] / (1.22 + [SPEC]) 

 where: the symbol || means “proportional to” 

 Substitution gives: 

 TIU (U.S. pregnant women) || x / (1.22 + (1.501 μmol/L) 

 TIU (U.S. pregnant women) || x / 2.721 

 TIU (U.S. pregnant women) || 0.368x 

Estimated TIU in Chilean Pregnant Women 

The TIU in the Chilean pregnant women is determined by substituting values into the 

Tonacchera Model. The [I-] is unknown but is directly related to the UIC. The median UIC of 

269 μg/L is 92% greater than in the U.S. pregnant women. The [I-

] in the Chilean pregnant 

women is assigned a value of “1.92x”. For simplicity of comparison to the United States, the 

Chilean pregnant mothers’ total NIS inhibition load from all three cities is averaged to 0.80 

μmol/L (i.e., (0.88 μmol/L + 0.79 μmol/L + 0.72 μmol/L) ÷ 3). 

Therefore, the TIU in the Chilean pregnant women is expressed by: 

 TIU (Chilean pregnant women) || [I-

] / (1.22 + [SPEC]) 

 Substitution gives: 

 TIU (Chilean pregnant women) || 1.92x / (1.22 + (0.80 μmol/L) 

 TIU (Chilean pregnant women) || 1.92x / 2.02 

 TIU (Chilean pregnant women) || 0.950x 

Percent Change in TIU of U.S. Pregnant Women as Compared to Chilean Pregnant 

Women 

The percent change in TIU of U.S. pregnant women as compared to Chilean pregnant 

women from the Tellez study is given by the following equation: 

% Change in TIU of U.S. Pregnant Women = U.S. TIU - Chilean TIU x 100% 

Chilean TIU 

 Substitution gives: 

% Change in TIU of U.S. Pregnant Women = ((0.368x - 0.950x)/ 0.950x) x 100% 

% Change in TIU of U.S. Pregnant Women = - 61% 

Therefore, the median U.S. pregnant woman has a 61% less TIU as compared to the 

Chilean pregnant women in the Tellez study. In other words, the U.S. median pregnant woman 

has only 39% of the amount of iodide uptake as her Chilean counterpart. In the Tellez study, the 

entire Chilean cohort had a reported median UIC of 269 μg/L, which is in the middle of the 

recommended UIC for pregnant and lactating women of 200-300 μg/L (Delange 2005, p 278, 

table 11E.8). The 61%TIU deficit is driven by the difference in the goitrogen load and iodide 

nutritional status between the United States and Chile. In other words, U.S. pregnant women 

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have about twice the goitrogen load as their Chilean counterparts, while having only about half 

the dietary intake of iodide. Both factors contribute to the decreased uptake of iodide by U.S. 

pregnant women. 

Relative Contribution of the TIU Deficit from Goitrogen Load and from Iodide 

Nutrition 

The Tonacchera Model can be used to assess the amount of TIU deficit attributed to the 

difference in the goitrogen load and to assess the amount of TIU deficit attributed to the 

difference in iodide nutrition. This is calculated by analyzing the contribution of each to the TIU 

separately. 

Change in TIU from the change in goitrogen load = ((0.368x - 0.495x)/ 0.495x) x 100% 

= - 25.7% 

Change in TIU from the change in iodide nutrition = ((x - 1.92x)/ 1.92x) x 100% 

= - 47.9% 

Note: The 26% and 48% are not added directly together to get the total 61% decrease TIU deficit 

value. They are combined mathematically in the following way to give 61%: 

Total Decrease = 1-((1-0.257)(1-0.479))

 = 1-((0.743)(0.521) 

 = 1-(0.387) 

 = 0.612 or 61% 

To further explain, of the original Chilean TIU, 26% is lost due to the increased U.S. goitrogen 

load leaving 0.74 TIU. Of the remaining 0.74 TIU, 48% of this amount is lost due to the 

decreased U.S. iodide nutrition leaving only 0.385 TIU (i.e., 0.74 – (0.74 x 0.48). This leaves 

39% of the original TIU, or a 61% decrease from the Chilean TIU (defined as 100% for this 

comparison). 

Therefore, the larger goitrogen load in the United States, by itself, causes the TIU to 

decrease by 61%. By contrast, the lower iodide nutritional status in the United States, by itself, 

causes the TIU to decrease by 48%. When the two factors (i.e., increased goitrogen load and 

decrease availability of iodide) act together, a 61% decrease in the TIU in the United States is 

predicted by the Tonacchera Model. 

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6.2 Crump Study 

The Crump study compared the thyroid hormone and TSH levels in 9,784 newborns and 

in 162 school-aged children in three Chilean cities (Crump 2000). The mean urinary iodide, 

TSH, and T3 levels were not statistically different in the schoolchildren among the three cities. 

However, the NAS Committee specifically commented, “Serum free T4 levels were significantly 

higher in children in Chanaral and Taltal then Antofagasta . . . the difference was opposite the 

direction predicted on the basis of competitive perchlorate inhibition of iodide uptake” (NAS 

2005, p 100). This contradiction in observed direction of the effect on free T4 levels should have 

raised an inquiry into reviewing the mechanism (i.e., because competitive inhibition from 

perchlorate only does not appear to explain the observed effect). Ideally, this should have 

triggered the possibility that a confounding variable was at work in the data (i.e., other NIS 

inhibitors). 

The potential confounding variable is the different levels of thiocyanate exposure 

observed in the Tellez study between Taltal and the other two cities. Based on the trend in 

amount of total NIS inhibition load observed across the three cities in the Tellez study (identified 

in the previous section), the trend in the serum free T4 levels in the Crump schoolchildren is in 

the direction predicted on the basis of total competitive inhibition of iodide uptake. Using the 

total goitrogen load better explains the trend in observations seen in the serum free T4 levels. 

The following table summarizes the study results in the schoolchildren: 

Summary of Crump Study Results of All Schoolchildren by City 

Parameter 

Antofagasta 

(n = 60) 

Chanaral 

(n = 60) 

Taltal 

(n = 60) 

Perchlorate Concentration in Drinking 

Water (μg/L) 

ND 

All samples < 4.0 μg/L 5.5 ± 1.6 111.6 ± 6.7 

Perchlorate Exposure very low group low group high group 

TSH (μU/ml) 3.3 ± 1.8 2.9 ± 1.3 3.0 ± 1.4 

Free T4 (ng/dL) 1.2 ± 0.1 1.3 ± 0.1 1.4 ± 0.2 

T3 (ng/dL) 208.6 ± 29.7 211.0 ± 20.9 212.0 ± 21.9 

Urinary Iodide (μg/L) 756 ± 404 614 ± 357 766 ± 474 

Est. Total NIS Inhibition Load 

in Pregnant Mothers in Tellez Study 1.54 μmol/L 1.37 μmol/L 1.14 μmol/L 

Relative Total NIS Inhibition Load 

Observed in Pregnant Mothers and 

Neonates in Tellez Study high medium low 

Source: Crump 2000, table 2. 

For the newborns in the Crump study, the newborn TSH levels were slightly lower in 

Taltal (highest perchlorate exposure group) as compared with the two low perchlorate exposure 

cities (p<0.001) (Crump 2000). Furthermore, the log serum TSH levels in the Taltal newborns 

were statistically lower than the other two cities (p<0.001); the log TSH levels did not vary 

significantly between the newborns in Antofagasta and Chanaral (Crump 2000; NAS 2005). 

Again, the NAS Committee specifically commented, “The lower mean in Taltal is, again, 

opposite in direction of what would be expected in association with increased exposure to 

perchlorate” (NAS 2005, p 101). Again, this contradiction in observed direction of the predicted 

inhibition effect of perchlorate on TSH levels should have raised an inquiry into reviewing the 

mechanism (i.e., competitive inhibition of perchlorate only does not appear to explain the 

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observed effect). Ideally, this should have triggered the possibility that a confounding variable is 

at work in the data (i.e., the other NIS inhibitors). 

 The potentially confounding variable is the different levels of thiocyanate exposure 

observed in the Tellez study between Taltal and the other two cities. Based on the trend in 

amount of total NIS inhibition load of pregnant mothers observed across the same three cities in 

the Tellez study, the trend in the TSH levels in the Crump neonates is in the direction predicted 

on the basis of the total competitive inhibition of iodide uptake in the pregnant mothers. 

Furthermore, by day 7, when the neonate’s thyroid is the sole influence on TSH level (i.e, 

mother’s residual influence is gone), the neonate TSH levels are essentially the same across the 

three cites (see table below). This mirrors the observation that the total goitrogen load estimated 

in the neonates from the 2005 Tellez study is also essentially the same across the three cities. 

Using the total goitrogen load better explains the observations seen in the serum TSH levels in 

the Taltal newborns than the perchlorate exposure level only. The following table summaries the 

study results in the neonates: 

Summary of Crump Study Results of Neonates by City 

Parameter 

Antofagasta 

(n = 8888) 

Chanaral 

(n = 468) 

Taltal 

(n = 428) 

Perchlorate Concentration in Drinking 

Water (μg/L) 

ND 

All samples < 4.0 μg/L 5.5 ± 1.6 111.6 ± 6.7 

Perchlorate Exposure Very low group low group high group 

TSH (μU/ml) Overall Both Genders 3.4 ± 7.8 3.0 ± 2.5 2.4 ± 1.9 

Estimated Total NIS Inhibition Load in 

Pregnant Mothers from the Tellez Study 0.88 μmol/L 0.79 μmol/L 0.72 μmol/L 

Relative Total NIS Inhibition Load 

Observed in Pregnant Mothers and 

Neonates in Tellez Study high medium low 

TSH (uU/ml) Day 7 Both Genders 2.4 ± 2.0 2.1 ± 1.4 2.1 ± 1.7 

Est. NIS Inhibition Load in Neonate from 

the Tellez Study 

(excluding nitrate - lack of data) 0.51 μmol/L 0.45 μmol/L 0.50 μmol/L 

Source: Crump 2000, table 8. 

According to the NAS Committee, the major criticisms of the Crump study indicated that 

the school-aged children had an iodide status different than those in the United States and a 

higher prevalence of goiter (NAS 2005, p 103). The mean urinary iodide excretion in the 

children was about 3 times higher than in the United States (NAS 2005, p 103). The NAS 

Committee finally concluded that the Crump study could be considered in evaluating perchlorate 

exposure in the United States (NAS 2005, p 105). 

The Crump study did not determine the amounts of nitrate or thiocyanate in any of the 

subjects. The NAS Committee notes the possibility of “uncontrolled confounders” in the Crump 

study as in any epidemiologic study (NAS 2005, p 103). Since the OIG has shown that the 

thiocyanate NIS inhibitor was an uncontrolled confounder in the Tellez study, this same 

confounder probably applies to the Crump study because it involves the same population from 

the same cites with the same potential difference in dietary habits and explains the observations 

better. 

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6.3 Conclusions 

The OIG’s analysis of the Tellez study shows the advantages of applying cumulative risk 

assessment to the environmental problem of perchlorate exposure. The biological step perturbed 

by perchlorate exposure is the uptake of iodide by the NIS. However, the uptake of iodide by the 

NIS is not just a function of exposure to perchlorate. The amount of iodide uptake by the NIS is 

the result of the combined effects of simultaneous exposure to all four anions: iodide, 

perchlorate, nitrate, and thiocyanate. The effects of each anion are defined by the Tonacchera 

Model, where TIU is proportional to [I-

] / (1.22 + [SPEC]). Measuring the internal indices of 

exposure (i.e., μmol/L concentration in serum) for iodide, perchlorate, nitrate, and thiocyanate is 

needed to more accurately characterize the amount of stress on the thyroid. 

The Chilean pregnant women and neonates have healthy thyroids because their iodide 

nutritional status is sufficient to tolerate their total goitrogen load. The fact that the relatively 

high exposure to 118 μg/day of perchlorate from water and food in Taltal represents only a small 

portion (11%) of their total goitrogen load, and to say that this level of perchlorate exposure did 

not generate thyroid health problems, is to miss the larger point. The potential impact of 

perchlorate exposure cannot be assessed without knowing the concurrent exposure to the other 

NIS inhibitors (nitrate and thiocyanate) and the iodide status of the population/individual. The 

essential finding from the Tellez study is that the total goitrogen load in Taltal (including the 

perchlorate) is small compared to the healthy iodide nutritional status. 

The critical information needed to characterize this public health problem is determining 

when the iodide nutritional level is insufficient to tolerate the total goitrogen load. The 

relationship between the iodide nutritional level and total goitrogen load is dynamic. As the 

availability of iodide increases, the tolerance for larger total goitrogen loads increases. In other 

words, iodide-deficient individuals cannot tolerate as much goitrogens as an individual with a 

healthy iodide intake. Defining when the iodide nutritional level is insufficient for the total 

goitrogen load and its impact on the regulation of perchlorate is the subject of a later section of 

this document. 

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7. Assessment of Total NIS Inhibitor Exposure 

7.1 Perchlorate Exposure 

To assess the role of perchlorate exposure on this public health issue, the amount of 

perchlorate exposure must be documented in adults, fetuses, and nursing neonates. 

7.1.1 Adults 

In 2006, Blount of the CDC, National Center for Environmental Health (NCEH), 

assessed the perchlorate exposure in the U.S. population using urinary biomonitoring data 

(Blount 2006a). As part of the 2001-2002 NHANES, a nationally representative population of 

2,820 U.S. residents (ages 6 years and older) provided urine samples for perchlorate testing. All 

2,820 urine samples tested found detectable levels of perchlorate (i.e., >0.05μg/L), indicating 

that perchlorate exposure in the U.S. population is common. Blount’s biomonitoring results are 

summarized below: 

Population 

Blount’s U.S. Perchlorate Exposure Assessment 

from 2001-2002 NHANES Using Urinary Biomonitoring Data 

Median 95th Percentile 

Adults 

(20 years and older) 

0.066 μg/kg-day 

(4.6 μg/day for a 70 kg adult) 

0.234 μg/kg-day 

(16.4 μg/day for a 70 kg adult) 

Reproductive Females 

(15-44 years old) 

0.057 μg/kg-day 

(4.0 μg/day for a 70 kg adult) 

0.214 μg/kg-day 

(15.0 μg/day for a 70 kg adult) 

Source: Blount 2006a. 

The perchlorate RfD is 0.7 μg/kg-day (equal to 0.0007 mg/kg-day). For a 70 kg adult, 

the perchlorate RfD allows the “safe” exposure to 49 μg of perchlorate per day for an adult. 

Therefore, the median perchlorate exposure is 9.4% and 8.1% of the perchlorate RfD in adults 

and females of reproductive age, respectively. Furthermore, the perchlorate exposure at the 95th 

percentile is 33% and 31% of the perchlorate RfD in adults and females of reproductive age, 

respectively. Therefore, the Blount biomonitoring study indicates that the perchlorate exposure 

in the majority of adults in the United States is well below the RfD. In fact, Blount’s 

biomonitoring study found that only 11 of the 1,618 adults (i.e., 20 years or older) tested had an 

estimated perchlorate exposure in excess of the perchlorate RfD of 0.7 μg/kg (i.e., 49 μg per 

day). This corresponds to about 0.7% of the adult U.S. population that might have perchlorate 

exposures greater than the RfD. 

In May 2007, the FDA’s Center for Food Safety and Applied Nutrition estimated the 

human dietary exposure to perchlorate from the consumption of 27 foods and beverages from 

samples collected in Fiscal Years 2004 and 2005. The preliminary human perchlorate dietary 

exposure assessment, “Preliminary Estimation of Perchlorate Dietary Exposure Based on FDA 

2004/2005 Exploratory Data,” was posted on FDA’s Website on May 31, 2007 (FDA 2007a). 

FDA’s preliminary testing represents only 32% of the food and 42% of the beverages in the diet. 

Since these samples targeted foods grown in areas known to have perchlorate present, the results 

from this study are not representative of total perchlorate exposures. The remaining 68% of the 

foods in the diet are expected to contain little to no perchlorate, although this assumption cannot 

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be verified. Using FDA’s stated assumption, FDA’s preliminary perchlorate dietary exposure 

results represent the bulk of the perchlorate exposure expected from the U.S. diet: 

Population 

FDA’s Preliminary Perchlorate Dietary Exposure Estimate 

Mean 90th Percentile 

All Ages (2 and up) 

0.053 μg/kg-day 

(3.7 μg/day for a 70 kg adult) 

0.12 μg/kg-day 

(8.4 μg/day for a 70 kg adult) 

Females (15-45 years) 

0.037 μg/kg-day 

(2.6 μg/day for a 70 kg adult) 

0.074 μg/kg-day 

(5.2 μg/day for a 70 kg adult) 

Source: FDA 2007a. 

On January 2, 2008, FDA published their TDS on perchlorate and iodide (Murray 2008). 

The TDS is an ongoing market basket survey in which 285 core foods (TDS foods) in the U.S. 

food supply are collected and analyzed to determine levels of various contaminants and nutrients 

in those foods. The foods collected in the TDS (referred to as the TDS food list) represent the 

major components of the diet of the U.S. population. The food list is based on results of national 

food consumption surveys and is updated from time to time to reflect changes in food 

consumption patterns. The FDA TDS reported the upper and lower bounds for the average 

dietary intakes of perchlorate for each of the 14 age/sex groups from FDA’s TDS samples 

collected in Fiscal Years 2005 and 2006. The upper and lower bounds for the average dietary 

intakes of perchlorate for infants 6 to 11 months and nonpregnant women 25 to 30 years are: 

Age/Sex Group Label 

FDA’s Total Dietary Study: Dietary Intake of Perchlorate 

Lower and Upper Bound 

AverageTotal Dietary Intake 

90th Percentile 

Total Dietary Intake 

Infants 

(6 to 11 months) 

0.26-0.29 μg/kg-day 

2.4 to 2.7 μg/day 

Not provided for 

in the TDS Design* 

Women 

(25 to 30 years) 

0.09 to 0.11 μg/kg-day 

5.4 to 6.8 μg/day 

Not provided for 

In the TDS Design* 

* FDA TDS is not designed to estimate intakes at the extremes (e.g., 10th or 90th percentiles). Murray 2008, p 8. 

Source: Murray 2008, table 5. 

The FDA TDS study has two significant limitations for characterizing the perchlorate 

exposure in a risk assessment. Perchlorate exposure during pregnancy and nursing is the critical 

period in which NIS stressor exposure could induce a low TIU resulting in an increased risk for 

adverse effects in the developing child. However, the FDA TDS does not provided estimates for 

dietary intakes for subgroups with specific nutritional needs (e.g., pregnant or lactating women). 

The second limitation is that the FDA TDS does not provide estimates for the distribution of 

perchlorate exposure within the age/sex group populations (e.g., 10th and 90th percentiles). 

Ideally, a risk assessment would benefit from an exposure estimate of the 90th percentile, but the 

FDA TDS does not provide this type of information. 

FDA’s human perchlorate preliminary dietary exposure assessment and the FDA TDS are 

in general agreement with the perchlorate exposure measured in Blount’s biomonitoring data. 

Specifically, FDA’s preliminary mean perchlorate exposure calculated for an adult is 3.7 μg/day. 

The FDA TDS estimated a lower and upper bound average total dietary intake for all age/sex 

groups ≥ 25 years old at 0.08 to 0.12 μg/kg-day (i.e., 5.6 to 8.4 μg/day for 70 kg adult) (Murray 

2008, table 5). These values agree with the median perchlorate exposure of 4.6 μg/day estimated 

from the Blount biomonitoring data. The average perchlorate exposures from the FDA 

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preliminary data and Blount biomonitoring data are less than 10% the perchlorate RfD of 49 

μg/day for an adult. Furthermore, FDA’s preliminary dietary exposure assessment at the 90th 

percentile is calculated at 8.4 μg/day or 17% of the RfD. The estimated perchlorate exposure at 

the 95th percentile using the Blount biomonitoring data is calculated at 16.4 μg/day, or 33% of 

the RfD. Both upper percentile values are significantly less than the perchlorate RfD of 49 

μg/day for an adult. 

7.1.2 Fetuses 

Assessing the perchlorate exposure in fetuses is difficult; direct measurements are not 

possible due to the risk to the child. Therefore, the use of PBPK modeling is required to predict 

the amount of exposure in the fetus. The Clewell Perchlorate PBPK Model has accurately 

predicted the serum perchlorate concentrations in sensitive populations including fetuses 

(Clewell 2007). The Clewell Perchlorate PBPK Model predictions for perchlorate serum 

concentrations were corroborated against pregnant women at the ~16 and ~32 week of gestation, 

fetuses at birth observed in the Tellez study, and 7.4-year-old schoolchildren observed in the 

Crump study (Clewell 2007) (see figure below). This use of the Clewell Perchlorate PBPK 

Model provides the ability to estimate the fetal perchlorate exposure based on the mother’s 

perchlorate exposure. 

Clewell Perchlorate PBPK Model Predicted Perchlorate Serum Concentrations 

The PBPK model predicted values (light grey) are the average ± SD (standard deviation). The 

measured perchlorate serum concentrations (dark grey) are the mean ± SD. The pregnant 

woman value is from the Tellez Chilean study (Tellez 2005). The 7.4-year-old child value is 

reported by Gibbs (Gibbs 2004) of the Chilean schoolchildren from the Crump study (Crump 

2000). 

Source: Clewell 2007, figure 10. 

The Clewell Perchlorate PBPK Model predicts that the internal perchlorate serum 

concentration in a fetus will be 5 times greater then the internal perchlorate serum concentration 

in an adult from an external perchlorate dose of 0.001 mg/kg-day (Clewell 2007, table 4). Using 

the Blount biomonitoring data to characterize the perchlorate exposure in U.S. population, if a 

pregnant woman is exposed to the median adult perchlorate exposure of 4.6 μg/day (i.e., 9.4% of 

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the RfD), the fetus would be expected have an internal perchlorate serum concentration that 

corresponds to 47% that of the RfD. Likewise, if a pregnant woman is exposed to the 95th 

percentile perchlorate exposure for an adult of 16.4 μg/day (i.e., 33% of the RfD), the fetus 

would be expected have an internal perchlorate serum concentration that corresponds to 1.67 

times the perchlorate RfD. Finally, if a pregnant woman is exposed to perchlorate at the RfD, 

the fetus would be expected have an internal perchlorate serum concentration that corresponds to 

5 times the perchlorate RfD. 

7.1.3 Nursing Neonates 

If exclusively breastfed, nursing infants are dependent on their mothers’ milk for all their 

nutrition, including the essential element, iodide. Both thyroidal and extrathyroidal NIS 

concentrate iodide from the serum into the thyroid by roughly the same magnitude (i.e., thyroid 

to serum ration (T/S) is 20- to 40-fold under steady-state conditions) (De La Vieja 2000, p 1093). 

In cases of iodide deficiency, the TSH stimulates the production of cyclic adenosine 

monophosphe (cAMP) in the thyroid to enhance the rate of active transport of iodide into the 

thyroid by the NIS (McMurray 1983, p 170). The T/S ratio may increase up to 300:1. TSH 

regulates the expression and activity of the NIS in the thyroid gland only (Merrill 2003; Clewell 

2003). TSH does not regulate NIS expression in the mammary gland or any other extrathyroidal 

tissue (Merrill 2003). The NIS expression and regulation appear to be controlled by prolactin 

and/or oxytocin (Merrill 2003). 

Nursing neonates are a sensitive population because an adequate supply of thyroid 

hormones is required for proper brain development. However, nursing neonates may be at a 

significant risk due to a relatively large perchlorate exposure (i.e., on a per-body-weight basis) 

due to the active concentration of perchlorate in breast milk by the NIS. Neonate perchlorate 

exposure is a function of the weight of the infant, the amount of milk consumption, and the 

perchlorate concentration of the milk. A 1-month-old infant’s median weight is 4.14 kg (EPA 

1997a) and these infants consume a mean intake of 673 ml of milk (Dewey 1983). A 6-monthold infant’s median weight is 7.53 kg (EPA 1997a), and those infants consume a mean intake of 

896 ml of milk (Dewey 1983). Therefore, the mean perchlorate concentration in breast milk that 

induces a perchlorate RfD exposure of 0.0007 mg/kg-day in a median sized neonate is: 

 For a 1-month-old infant: 

(0.7 μg/kg-day x 4.14 kg body weight) ÷ 0.673 L of milk/day = 4.3 μg/L 

 For a 6-month-old infant: 

(0.7 μg/kg-day x 7.53 kg body weight) ÷ 0.896 L of milk/day = 5.9 μg/L 

In fall 2003 and spring 2004, Kirk evaluated the concentrations of perchlorate and iodide 

in the breast milk of 36 healthy women across 18 States and 23 healthy women across 14 States, 

respectively (Kirk 2007). The following table summaries the study results for the concentration 

of perchlorate and iodide found in human breast milk: 

81
 
10-P-0101 

Analyte 

Perchlorate and Iodide Concentrations in Human Breast Milk 

Number of 

Subjects (n) 

Range 

(μg/L) 

Mean * 

(μg/L) 

Median 

(μg/L) 

Perchlorate 36 1.4 to 92.2 10.5 ± n/a 3.3 

Iodide 23 4.5 to 184.5 63.3 ± n/a 33.5 

* No mean statistics provided in the paper. The paper provided an average for each test subject comprising 4 to 6 

samples per subject. 

Source: Kirk 2005. 

Published in February 2007, Kirk evaluated the concentrations of perchlorate, 

thiocyanate, and iodide in the breast milk of 10 nonsmoking lactating women with five subjects 

from the Texas Panhandle and one subject from each of the following States: Colorado, Florida, 

Missouri, New Mexico, and North Carolina (Kirk 2007). Using an average milk consumption of 

100 ml/kg-day, the authors found that 3 of 10 subjects averaged breast milk perchlorate 

concentrations above 7 μg/L, which would cause these 3 infants to exceed the perchlorate RfD of 

0.7 μg/kg-day. As the infant grows, the infant’s exposure per unit weight decreases. The 

authors project that an average weight infant consuming an average amount of milk would 

exceed the perchlorate RfD for the first 2 months of life. Furthermore, the authors found that the 

median iodide concentration of 55.2 μg/L is substantially below the recommended level of 110­

130 μg/day. The following table summarizes the study’s results for the concentration of 

perchlorate and iodide found in human breast milk: 

Analyte 

Perchlorate and Iodide Concentrations in Human Breast Milk 

in 10 Nonsmoking Women 

Number of 

sample (n) 

Range 

(μg/L) 

Mean ± SD 

(μg/L) 

Median 

(μg/L) 

Perchlorate 147 0.5 to 39.5 5.8 ± 6.2 4.0 

Iodide 108 3.1 to 334 87.9 ± 80.9 55.2 

Source: Kirk 2007. 

Between July 2002 and April 2006, breast milk and urine of 57 healthy lactating women 

in the Boston area were analyzed for perchlorate and iodide concentrations (Pearce 2007). The 

following table summaries the study’s results for the concentration of perchlorate and iodide 

found in human breast milk: 

Analyte 

Perchlorate and Iodide Concentrations in Breast Milk and Urine Samples 

from 57 Healthy Boston Women 

Number of 

sample (n) 

Range 

(μg/L) 

Mean ± SD 

(μg/L) 

Median 

(μg/L) 

Perchlorate 49 1.3 to 411 33 ± 77 9.1 

Urinary Perchlorate 56 0.37 to 127 8.2 ± 19 3.0 

Iodide 57 2.7 to 1968 205 ± 271 155 

Urinary Iodide 57 25 to 920 155 ± 142 114 

Source: Pearce 2007. 

82
 
10-P-0101 

Estimate Using the Clewell Perchlorate PBPK Model 

The Clewell Perchlorate PBPK Model predicts that the internal perchlorate serum 

concentration in a 1.5-month-old nursing neonate will be 4 times greater then the internal 

perchlorate serum concentration in an adult from an external perchlorate dose of 0.001 mg/kgday (Clewell 2007, table 4). Using the Blount biomonitoring data to characterize the perchlorate 

exposure in the U.S. population, if a pregnant woman is exposed to the median adult perchlorate 

exposure of 4.6 μg/day (i.e., 9.4% of the RfD), the nursing neonate would be expected to have an 

internal perchlorate serum concentration that corresponds to 37% that of the RfD. Likewise, if a 

pregnant woman is exposed to the 95th percentile perchlorate exposure for an adult of 16.4 

μg/day (i.e., 33% of the RfD), the nursing neonate would be expected have an internal 

perchlorate serum concentration that corresponds to 1.34 times the perchlorate RfD. Finally, if a 

pregnant woman is exposed to perchlorate at the RfD, the nursing neonate would be expected 

have an internal perchlorate serum concentration that corresponds to 4 times the perchlorate RfD. 

7.2 Total NIS Inhibitor Exposure 

Since perchlorate is not the only NIS inhibitor to which these three groups are exposed, 

the perchlorate exposure must be evaluated in context with the total amount of NIS inhibition on 

the body (i.e., the goitrogen load). To determine the total goitrogen load, the concurrent amount 

of exposure to thiocyanate and nitrate must be estimated in each of these groups. Knowing the 

exposure to each NIS inhibitor in each group allows the total goitrogen load to be determined for 

each group to assess the contribution of perchlorate to the body’s total goitrogen load. 

Furthermore, the Tonacchera Model also quantifies the impact of the availability of iodide on the 

thyroid’s ability to uptake iodide. Therefore, the iodide nutrition status of each group must be 

determined and evaluated (see Section 8 of this document). 

7.2.1 Total NIS Inhibition Load Acting on Adults 

The total NIS inhibition load (i.e., total goitrogen load) acting on the body is determined 

by knowing the serum concentration of the three environmentally prominent NIS inhibitors: 

perchlorate, nitrate, and thiocyanate. The serum concentration of each is then used to calculate 

the SPEC. 

The perchlorate serum concentration in an adult was predicted using the Clewell 

Perchlorate PBPK Model (Clewell 2007). The perchlorate RfD was dervived by applying a 10­

fold UF to the NOEL of 7 μg/kg-day measured in Greer’s subjects (NAS 2005, p 15). Therefore, 

the perchlorate NOEL corresponds to an external dose of 490 μg/day. The closest point 

provided in Clewell’s paper is that an external dose of 700 μg/day is predicted to generate a 

perchlorate serum concentration of 10 μg/L in an adult (Clewell 2007, table 4). If this value is 

linearly scaled down to the perchlorate NOEL of 490 μg/day in an adult (i.e., 7 μg/kg-day), the 

predicted perchlorate serum concentrations at the NOEL in an adult would be about 7 μg/L (i.e., 

0.070 μmol/L). Likewise, the Clewell Perchlorate PBPK Model predicts a perchlorate serum of 

2 μg/L for an adult at an external dose of 70 μg/day (i.e., 1 μg/kg-day or 1.42 times the RfD) 

(Clewell 2007). If this value is linearly scaled down to the EPA RfD of 49 μg/day in an adult 

(i.e., 0.7 μg/kg-day), the predicted perchlorate serum concentrations at EPA’s RfD in an adult 

83
 
 

 

 

 

 

 

10-P-0101 

would be 1.4 μg/L (i.e., 0.014 μmol/L). If this Clewell data is scaled down to the 95th percentile 

of the U.S. perchlorate exposure level of 16.4 μg/day in an adult measured in the Blount 

biomonitoring study, the predicted perchlorate serum concentrations at 95th percentile of the 

U.S. perchlorate exposure level in an adult would be 0.47 μg/L (i.e., 0.0047 μmol/L)(Blount 

2006a). If the Clewell data are scaled down to the median U.S. perchlorate exposure level of 4.6 

μg/day in an adult measured in the Blount biomonitoring study, the predicted perchlorate serum 

concentrations at median U.S. perchlorate exposure level in an adult would be 0.13 μg/L (i.e., 

0.0013 μmol/L)) (Blount 2006a). The following table summarizes the predicted perchlorate 

serum concentrations in an adult using the Clewell Perchlorate PBPK Model: 

Perchlorate Exposure Level 

External Perchlorate Dose 

in an a 70 kg Adult 

(μg/day) 

Predicted Perchlorate Serum 

Concentration in an Adult 

NOEL (7 μg/kg-day) 490 7.0 μg/L or 0.070 μmol/L 

RfD (0.7 μg/kg-day) 49 1.4 μg/L or 0.014 μmol/L 

95th Percentile 16.4 0.47 μg/L or 0.0047 μmol/L 

50th Percentile 4.6 0.13 μg/L or 0.0013 μmol/L 

Source: OIG Analysis. 

In the Western world, the typical nitrate serum concentration ranges from 10-140 

μmol/L, with the mean nitrate serum concentration being between 30-50 μmol/L (Tonacchera 

2004). Thiocyanate serum concentration in nonsmokers is typically in the range of 10-70 

μmol/L. By contrast, the thiocyanate serum concentration of smokers is higher and is typically 

in the range of 80-120 μmol/L (Tonacchera 2004). A thiocyanate serum concentration of 40.5 

μmol/L was observed in the controls in Braverman’s study of workers at the ammonium 

perchlorate plant in Cedar City, Utah (Bravermen 2005). Therefore, although variable, the 

typical nitrate and thiocyanate serum concentrations in the U.S. population are 40 μmol/L and 40 

μmol/L, respectively. These values will be used for the calculation of the total NIS inhibition 

load in a U.S. adult. 

The total NIS inhibition load (i.e., total goitrogen load) acting on the body is determined 

by calculating the SPEC. The SPEC is calculated as follows (concept taken from Tonacchera 

2004): 

SPEC = (Amt of ClO4

-

 Inhibition) + (Amt of NO3

-

 Inhibition) + (Amt of free SCN- Inhibition) 

SPEC = [ClO4

-

] + [NO3

-

] /240 + [free SCN-] /15 

Where: [ ] is molarity 

Serum inhibition potency of perchlorate = 1 

Serum inhibition potency of nitrate relative to perchlorate = 1/240 

Serum inhibition potency of thiocyanate relative to perchlorate = 1/15 

The following are calculations for the total NIS inhibition in a U.S. adult at the NOEL, 

RfD, 95th percentile, and median perchlorate exposure levels expressed as SPECs: 

84
 
 

 

 

 

 

 

 

10-P-0101 

SPEC (at NOEL) = 0.070 μmol/L + (40 μmol/L ÷ 240) + (40 μmol/L x 0.5 free SCN- ÷ 15) 

= 0.070 μmol/L + 0.167 μmol/L + 1.333 μmol/L 

 = 1.567 μmol/L 

SPEC (at RfD) = 0.014 μmol/L + (40 μmol/L ÷ 240) + (40 μmol/L x 0.5 free SCN-

 ÷ 15) 

= 0.014 μmol/L + 0.167 μmol/L + 1.333 μmol/L 

 = 1.511 μmol/L 

SPEC (at 95th CLO4

-

) = 0.0047 μmol/L + (40 μmol/L ÷ 240) + (40 μmol/L x 0.5 free SCN- ÷ 15) 

= 0.0047 μmol/L + 0.167μmol/L + 1.333 μmol/L 

 = 1.505 μmol/L 

 SPEC (median ClO4

-

) = 0.0013 μmol/L + (40 μmol/L ÷ 240) + (40 μmol/L x 0.5 free SCN- ÷ 15) 

= 0.0013 μmol/L + 0.167 μmol/L + 1.333 μmol/L 

 = 1.501 μmol/L 

SPEC (w/no ClO4

-

) = 0.0 μmol/L + (40.0 μmol/L ÷ 240) + (40.0 μmol/L x 0.5 free SCN- ÷ 15) 

= 0.0000 μmol/L + 0.1667 μmol/L + 1.333 μmol/L 

 = 1.500 μmol/L 

The following table summarizes the total NIS inhibition in a typical U.S. adult having 40 

μmoles/L exposures to both nitrate and thiocyanate at various levels of perchlorate exposure. 

Furthermore, the table identifies the relative contribution of each NIS inhibitor to the total NIS 

inhibition: 

Relative Contribution of Each NIS Inhibitor 

to the Total Amount of NIS Inhibition in an Adult 

Perchlorate 

Exposure Level 

Total Amount of 

NIS Inhibition in 

an Adult 

(SPEC) Perchlorate 

Nitrate 

at 

(40 μmoles/L) 

Thiocyanate 

at 

(40 μmoles/L) 

At the Perchlorate NOEL 

(7 μg/kg-day) 

1.567 μmoles/L 4.5% 10.7% 85.1% 

At the Perchlorate RfD of 

(0.7 μg/kg-day) 

1.511 μmoles/L 0.93% 11.1% 88.2% 

95th percentile of U.S. 

population (Blount 2006) 

1.505 μmoles/L 0.31% 11.1% 88.6% 

50th percentile of U.S. 

population (Blount 2006) 

1.501 μmoles/L 0.09% 11.1% 88.8% 

Zero Perchlorate 1.500 μmoles/L 0.00% 11.1% 88.9% 

Source: OIG Analysis. 

The Tonacchera Model establishes a mathematical equation to calculate the TIU of the 

NIS from the serum concentrations of the three NIS inhibitors: perchlorate, nitrate, and 

thiocyanate. The iodide concentration in the serum (i.e., [I-

]) is unknown but should be directly 

related to the UIC. Therefore, [I-] is assigned a value of “x” in these calculations. The following 

calculates the TIU at the perchlorate exposure of zero (theoretical) and at the RfD and the 

amount of change in TIU from the exposure of perchlorate at the RfD and at the NOEL: 

85
 
 

 

 

 

 

 

 

10-P-0101 

The TIU with no perchlorate exposure is expressed by: 

 TIU (w/ no Perchlorate Exposure) || [I-

] / (1.22 + [SPEC]) 

 where: the symbol || means “proportional to” 

 Substitution gives: 

 TIU (w/ no Perchlorate Exposure) || x / (1.22 + 1.500μmol/L) 

 TIU (w/ no Perchlorate Exposure) || x / 2.720 

 TIU (w/ no Perchlorate Exposure) || 0.3676x 

The TIU at a perchlorate exposure level of the RfD is expressed by: 

 TIU (Perchlorate Exposure at RfD) || [I-

] / (1.22 + [SPEC])

 Substitution gives: 

 TIU (Perchlorate Exposure at RfD) || x / (1.22 + 1.511 μmol/L) 

 TIU (Perchlorate Exposure at RfD) || x / 2.731 

 TIU (Perchlorate Exposure at RfD) || 0.3662x 

The change in TIU with perchlorate exposure at RfD = TIU (RfD) - TIU (no ClO4

-

) x 100% 

TIU (no ClO4

-

) 

 Substitution gives: 

Change in TIU at perchlorate RfD = ((0.3662x - 0.3676x)/ 0.3676x) x 100% 

Change in TIU at perchlorate RfD = - 0.38% (i.e., a decrease of 0.4 %) 

The TIU at a perchlorate exposure level of the NOEL is expressed by: 

 TIU (Perchlorate Exposure at NOEL) || [I-] / (1.22 + [SPEC]) 

 Substitution gives: 

 TIU (Perchlorate Exposure at NOEL) || x / (1.22 + 1.567 μmol/L) 

 TIU (Perchlorate Exposure at NOEL) || x / 2.787 

 TIU (Perchlorate Exposure at NOEL) || 0.3588x 

Change in TIU with perchlorate exposure at RfD = TIU (NOEL) - TIU (no ClO4

-

) x 100% 

TIU (no ClO4

-

) 

 Substitution gives: 

Change in TIU at perchlorate RfD = ((0.3588x - 0.3676x)/ 0.3676x) x 100% 

Change in TIU at perchlorate RfD = - 2.4% (i.e., a decrease of 2.4 %) 

In a typical adult with nitrate and thiocyanate exposures of 40 μmoles/L exposures, the 

above calculations predict that the exposure to perchlorate at the RfD or at the NOEL will 

decrease the uptake of iodide by the thyroid by 0.4% and 1.9%, respectively. However, the 

Tonacchera Model predicts TIU is proportional to [I-

] for all levels of iodide nutrition for any 

fixed underlying goitrogen load between 0.1 μmol/L to about 12 μmol/L PEC. The TIU vs log 

PEC relationship becomes nonlinear above 12 μmol/L PEC (Tonacchera 2004, figure 2). 

Therefore, the TIU could remain unchanged at the perchlorate exposure level of the RfD and at 

the NOEL in an adult if “x” (iodide concentration in the serum) increases by 0.4% and 2.4%, 

respectively. 

86
 
 

10-P-0101 

Seasonal and Dietary Variation in NIS Inhibitor Load 

By comparison, consumption of common vegetables is a significant and natural source of 

thiocyanates. In a Norwegian health study of 25,300 people, the mean thiocyanate serum levels 

(± SD) were 33.9 ± 14.0 μmol/L and 33.4 ± 14.0 μmol/L in nonsmoking males and females, 

respectively (Foss 1986). The thiocyanate serum levels in 95% of the nonsmokers ranged 

from10 μmol/L to 60μmol/L. Foods particularly rich in thiocyanate include cabbage, broccoli, 

Brussels sprouts, corn (maize), turnips, rapeseed, and mustard seed. Foods are known to contain 

varying quantities of thiocyanate and the content varies considerably from sample to sample. An 

individual’s thiocyanate serum level will vary depending on the frequency and amount of 

consumption of thiocyanate-containing food types. 

For example, a nonsmoking individual consumed 100 grams of raw Brussels sprouts each 

day for a week to document a rise in thiocyanate serum levels from 31 to 80 μmol/L. Dietary 

thiocyanate exposure also exhibits a change of about 10 μmol/L, presumably due to seasonal 

changes in the composition of the diet (Foss 1986). Cabbage is a high thiocyanate content food 

with consumption higher during autumn than any other time of year. The following table 

demonstrates the seasonality of thiocyanate serum levels in nonsmokers: 

Study Group 

Serum Thiocyanate (μmol/L) 

1st Quarter 

of the Year 

2nd Quarter 

of the Year 

3rd Quarter 

of the Year 

4th Quarter 

of the Year 

Nonsmoking Males (n = 6212) 29.5 30.2 39.4 39.4 

Nonsmoking Females (n = 7908) 29.9 30.1 39.9 39.4 

Source: Foss 1986. 

The purpose of reviewing natural thiocyanate exposure from the diet is to show that a 10 

μmol/L change in human thiocyanate serum levels is common. Both the nonsmoking males and 

females in the Norwegian health study had a ± 14.0 μmol/L SD with regard to the mean (Foss 

1986). Furthermore, the seasonal change in thiocyanate serum level in the Norwegian 

nonsmokers was about 10.0 μmol/L. 

In regard to the amount of NIS inhibition, a change of 10.0 μmol/L in human thiocyanate 

serum levels represents a much greater amount of NIS inhibition than exposure to perchlorate at 

the RfD in an adult. The amount of NIS inhibition of 10.0 μmol/L in human thiocyanate serum 

is measured by the Tonacchera Model as SPEC and has value of 0.333 μmol/L (i.e., (10 μmol/L 

x 0.5 free SCN-

) ÷ 15). By comparison, perchlorate exposure at the RfD has an estimated SPEC 

of 0.014 μmol/L. Therefore, the fluctuation in the human thiocyanate serum of 10.0 μmol/L 

causes a change in the amount of NIS inhibition that is about 24 times greater than the amount of 

NIS inhibition caused by perchlorate exposure at the RfD. 

7.2.2 Total NIS Inhibition Load Acting on Fetuses 

The total NIS inhibition load (i.e., total goitrogen load) acting on the fetus is determined 

by estimating the serum concentration in the fetus of the three environmentally prominent NIS 

inhibitors: perchlorate, nitrate, and thiocyanate. The serum concentration of each is then used to 

calculate the SPEC in the fetus. Direct measurements of fetal exposures to each of the NIS 

87
 
 

 

 

 

 

 

 

 

 

10-P-0101 

inhibitors are not possible due to the unacceptable risk to the unborn child. However, a direct 

measurement of serum concentration is possible at birth without risk to the fetus by measuring 

the serum concentration in umbilical cord blood. 

 The fetal thiocyanate serum concentration can be estimated by direct measurements of 

thiocyanate in both maternal and cord serums that have been reported in at least four studies (see 

table below). The thiocyanate ratio of cord serum to maternal serum observed in nonsmokers is 

71%, 88%, and 92% observed in the Hauth, Laurberg, and Vanderpass studies, respectively 

(Hauth 1984; Laurberg 2004; Vanderpass 1984). For estimating the fetal thiocyanate serum 

concentration, the thiocyanate ratio of cord serum to maternal serum of 71% observed in the 

nonsmokers from the Hauth study is used (Hauth 1984). Using the thiocyanate ratio of cord 

serum to maternal serum of 71% provides the lowest expected value in the fetal thiocyanate 

serum concentration (i.e., use of either 88% or 92% to estimate the fetal thiocyanate serum 

concentration would decrease the relative contribution of NIS inhibition from perchlorate). The 

fetal thiocyanate serum concentration is estimated by multiplying the typical thiocyanate serum 

concentration found in the Western world of 40 μmol/L by the thiocyanate ratio of cord serum to 

maternal serum of 71%. Therefore, the typical fetal thiocyanate serum concentration in the 

Western world is estimated to be at least 28.4 μmol/L. This estimated fetal thiocyanate serum 

concentration is a conservative value and is based on the direct thiocyanate measures observed in 

cord blood. 

Study

 (Exposure Type/Description) 

Mother’s 

SCNSerum 

Concentration 

(μmol/L) 

Cord SCNSerum 

Concentration 

(μmol/L) 

SCN Ratio 

Cord Serum/Mother Serum 

Hauth 1984 

 Smokers

 Passive Smokers

 Nonsmokers 

95 

35.9 

32.3 

72 

26 

23 

76% 

72% 

71% 

Laurberg 2004

 Smokers

 Nonsmokers 

84.9 ± 25.4 

54.7 ± 18.2 

94.6 ± 31.9 

48.3 ± 15.5 

111% 

88% 

Nafstad 1995 

 24 Smokers & 4 Nonsmokers 69 47 68% 

Vanderpass 1984 

 Central Africa (dietary SCN)

 Belgian Controls 

133 ± 7 

36 ± 7 

134 ± 2 

33 ± 7 

101% 

92% 

Sources: Hauth 1984; Laurberg 2004; Nafstad 1995; Vanderpass 1984. 

The Clewell PBPK model predicts a perchlorate serum concentration (i.e., an internal 

indice) of 1.4 μg/L (i.e., 0.014 μmol/L) in an adult at an external exposure dose at the RfD. The 

Clewell PBPK model predicts a pregnant woman’s perchlorate serum concentration as being 2.5 

times greater than an adult’s perchlorate serum concentration at an external exposure dose at the 

RfD which corresponds to 3.5 μg/L or 0.035 μmol/L. Likewise, the Clewell PBPK model 

predicts a fetus’s perchlorate serum concentration as being 5 times greater than an adult’s 

perchlorate serum concentration at an external exposure dose at the RfD which corresponds to 7 

μg/L or 0.070 μmol/L. 

88
 
 

 

 

 

10-P-0101 

Although NIS is present in the placenta, the transport of nitrate from the mother’s blood 

to the fetal blood would be expected (i.e., analogous to the known transport of nitrate from 

maternal blood into breast milk). However, the OIG could not find a study that reports the 

amount of nitrate found in cord blood. Although nitrate contributes to fetal NIS inhibition, the 

amount of NIS inhibition from nitrate is problematic to estimate and is not used in the following 

calculation of the total NIS inhibition load on the fetal thyroid with a perchlorate exposure at the 

RfD: 

SPEC(RfD) = 0.070 μmol/L + (μmol/L of NO3

-

 unknown) + ((40 μmol/L x 0.71 ratio) x 0.5 ÷ 15) 

 = 0.070 μmol/L + (μmol/L of NO3

-

 unknown) + ((28.4 μmol/L) x 0.5 ÷ 15) 

 = 0.070 μmol/L + (NO3

-

 contribution unknown) + 0.947 μmol/L 

 = 1.017 μmol/L 

In a fetus, the perchlorate at the RfD contributes about 6.9% of the total NIS inhibition 

load acting on the thyroid. (Note: With the contribution from nitrate or the use of a higher SCNmaternal/cord serum ratio, this estimated value will be smaller.) 

The TIU of the fetus with the mother having an external exposure dose at the RfD is 

expressed by: 

 TIU (Fetus) || [I-] / (1.22 + [SPEC]) 

 Substitution gives: 

 TIU (Fetus) || x / (1.22 + 1.017 μmol/L) 

 TIU (Fetus) || x / 2.237 

 TIU (Fetus) || 0.4470x 

The TIU of the fetus with the mother having no perchlorate exposure is expressed by: 

 TIU (Fetus with no perchlorate exposure) || [I-

] / (1.22 + [SPEC]) 

 Substitution gives: 

 TIU (Fetus with no perchlorate exposure) || x / (1.22 + 0.947 μmol/L) 

 TIU (Fetus with no perchlorate exposure) || x / 2.167 

 TIU (Fetus with no perchlorate exposure) || 0.4615x 

The change in %TIU(Fetus) with mother exposed at RfD versus no perchlorate exposure is 

given by: 

= TIU (Fetus with exposure) - TIU (Fetus with no ClO4

-

) x 100% 

TIU(fetus with no ClO4

-

) 

89
 
 

10-P-0101 

Substitution gives: 

%TIU(Fetus) w/ mother exposed at RfD = ((0.4470x - 0.4615x)/ 0.4615x) x 100% 

= - 3.1% (i.e., a decrease of 3.1 %) 

(Note: With the contribution from nitrate, this estimated value will be < 3.1%.) 

7.2.3 Total NIS Inhibition Load Acting on Nursing Infants 

The total NIS inhibition load acting on nursing infant’s thyroid at a perchlorate RfD 

exposure to the nursing mother can be estimated by adding the amount of NIS inhibition 

contributed from perchlorate, nitrate, and thiocyanate together. All three of these NIS inhibitors 

are found in human breast milk. 

In regard to thiocyanate in breast milk, a Norwegian study reported the mean thiocyanate 

concentration in breast milk as 9.0 mg/L in smokers and 10.5 mg/L in nonsmokers (Dorea 2004). 

By contrast, the mean thiocyanate concentration in breast milk in the United States is reported to 

be 4.2 mg/L in smokers and 0.92 mg/L in nonsmokers (Dorea 2004). The reported thiocyanate 

concentrations in breast milk in nonsmokers, which range from a low of 0.92 mg/L to a high of 

10.5 mg/L, are large (i.e., an order of magnitude), which introduces a lot of uncertainty into the 

estimation. For purposes of estimating (i.e., a conservative estimate) the total NIS inhibition 

load acting on nursing infant’s thyroid at a perchlorate RfD exposure to the nursing mother, the 

mean thiocyanate concentration in breast milk in the United States of 0.92 mg/L in nonsmokers 

will be used. 

In regard to nitrate concentrations in breast milk, 20 healthy, lactating women in the State 

of Iowa had their breast milk sampled and tested for nitrate (Dusdieker 1996). The study found 

4.4 ± 3.6 mg nitrate/L in human milk (Dusdieker 1996). 

The concentration of perchlorate in breast milk when the lactating mother is exposed to 

perchlorate at the RfD is estimated from the perchlorate PBPK podel in rats. The perchlorate 

PBPK model in rats predicts that about 50% of the daily maternal perchlorate dose at 0.01 

mg/kg-day is transferred to the nursing pup through breast milk (Clewell 2003, 416, (language in 

the abstract)). If the same relationship holds in humans, lactating women exposed at the 

perchlorate RfD (i.e., 49 μg/day) would be predicted to transfer 24.5 μg perchlorate/day to the 

nursing infant. Neonate perchlorate exposure is a function of both the weight of the infant, the 

amount of milk consumption, and the perchlorate concentration of the milk. A 1-month-old 

infant’s median weight is 4.14 kg (EPA 1997a) and that infant consumes a mean intake of 673 

ml of milk (Dewey 1983). A 6-month-old infant’s median weight is 7.53 kg (EPA 1997a) and 

that infant consumes a mean intake of 673 ml of milk (Dewey 1983). Since a 1-month-old infant 

consumes 0.673 L of milk/day, a breast milk concentration of 36.4 μg perchlorate/L transfers 

24.5 μg perchlorate/day to the nursing infant (i.e., the 50% transfer the mother’s RfD perchlorate 

exposure to the nursing infant predicted by the PBPK model). Likewise, a 6-month-old infant 

consumes 0.896 L of milk/day, a breast milk concentration of 27.3 μg perchlorate/L transfers 

24.5 μg perchlorate/day to the nursing infant. 

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The total NIS inhibition load acting on a nursing infant’s thyroid at a perchlorate RfD 

exposure to the nursing mother estimates perchlorate breast milk concentrations of 36.4 μg/L for 

a 1-month-old and 27.3 μg/L for a 6-month-old (i.e., perchlorate concentration in breast milk is 

estimated to be higher because less milk volume is generated to meet the child’s needs). These 

PBPK model estimates of 36.4 μg/L and 27.3 μg/L for perchlorate concentrations in human 

breast milk are substantially above the measured median perchlorate concentrations in human 

breast milk of 3.3 μg/L, 4.0 μg/L and 9.1 μg/L (Kirk 2005; Kirk 2007; Pearce 2007). The 

exposure to each of the NIS inhibitors found in human breast milk is estimated as follows: 

For a 1-month-old infant: 

36.4 μg ClO4-/L x 0.673 L of milk/day = 24.5 μg ClO4-/day 

920 μg SCN-

/L x 0.673 L of milk/day = 619 μg SCN- /day 

 4400 μg NO3

-

/L x 0.673 L of milk/day = 2961 μg nitrate/day 

For a 6-month-old infant: 

27.3 μg ClO4-/L x 0.896 L of milk/day = 24.5 μg ClO4-/day 

920 μg SCN-/L x 0.896 L of milk/day = 824 μg SCN- /day 

 4400 μg NO3

-

/L x 0.896 L of milk/day = 3942.4 μg nitrate/day 

The total NIS inhibitory effect measured upon ingestion of the NIS inhibitors is given by 

the following OPEC equation (concept adapted from Tonacchera 2004; De Groef 2006, 155): 

OPEC = (Amt of ClO4- Inhibition) + (Amt of NO3- Inhibition) + (Amt of SCN- Inhibition) 

OPEC = grams perchlorate + grams nitrate/150 + 0.5 free SCN- x grams thiocyanate/8.8 

OPEC = grams perchlorate + grams nitrate/150 + grams thiocyanate/17.6 

Where: 

Oral inhibition potency of perchlorate = 1 

Oral inhibition potency of nitrate relative to perchlorate = 1/150 

Oral inhibition potency of thiocyanate relative to perchlorate = 0.5/8.8 = 1/17.6 

The total NIS inhibition load acting on nursing infant’s thyroid at a perchlorate RfD 

exposure to the nursing mother is estimated as follows: 

For a 1-month-old infant: 

OPEC(1 month) = (Amt ClO4-

 Inhibition) + (Amt of NO3- Inhibition) + (Amt of SCNInhibition) 

OPEC(1 month) = μg perchlorate + μg nitrate/150 + μg thiocyanate/17.6 

OPEC(1 month) = 24.5 μg ClO4-

/day + 2961 μg nitrate/day ÷ 150 + 619 μg SCN- /day ÷ 17.6 

OPEC(1 month) = 24.5 μg ClO4

-

/day + 19.74 μg ClO4

-

equiv./day + 35.2 μg ClO4

-

equiv./day 

OPEC(1 month) = 79.4 μg ClO4

-

equivalent/day 

For a 6-month-old infant: 

OPEC(6 month) = (Amt ClO4-

 Inhibition) + (Amt of NO3- Inhibition) + (Amt of SCNInhibition) 

OPEC(6 month) = μg perchlorate + μg nitrate/150 + μg thiocyanate/17.6 

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OPEC(6 month) = 24.5 μg ClO4-/day + 3942.4 μg nitrate/day ÷ 150 + 824 μg SCN- /day ÷ 17.6 

OPEC(6 month) = 24.5 μg ClO4

-

/day + 26.3 μg ClO4

-

equiv./day + 46.8 μg ClO4

-

equiv./day 

OPEC(6 month) = 97.6 μg ClO4

-

equivalent/day 

At both 1 month and 6 months, thiocyanate exposure in breast milk contributes the 

largest portion of the NIS inhibition. These OPEC values were calculated using the lower 

estimated thiocyanate concentration in breast milk of 0.92 mg/L in nonsmokers. The OPEC 

values would be much larger if the higher estimated thiocyanate concentration in breast milk of 

10.5 mg/L in nonsmokers was used. Using the lowest thiocyanate exposure at 1 month, maternal 

perchlorate exposure at the RfD is estimated to result in perchlorate contributing about 30% of 

the nursing infant’s total NIS inhibition load. Using the lowest thiocyanate exposure at 6 

months, maternal perchlorate exposure at the RfD is estimated to result in perchlorate 

contributing about 25% of the nursing infant’s total NIS inhibition load. 

This characterization of a nursing infant’s total NIS inhibition load clearly indicates that 

perchlorate is not acting alone and the use of a single chemical risk assessment of perchlorate to 

characterize the risk of NIS inhibition acting on a nursing infant’s thyroid is incomplete. A 

cumulative risk assessment approach is needed to characterize and understand the sources and 

total risk of NIS inhibition acting on a nursing infant’s thyroid. Furthermore, a cumulative risk 

assessment approach is needed to quantify the effect of all four NIS stressor on the TIU by the 

nursing infant. 

7.2.4 Total NIS Inhibition Load Acting on Non-nursing Infants 

To calculate or estimate the total NIS inhibition load (i.e., total goitrogen load) acting on 

the thyroid of non-nursing infants, the non-nursing infant exposure to each of the three 

environmentally prominent NIS inhibitors (i.e., thiocyanate, nitrate, and perchlorate) must be 

known. Unfortunately, neither the serum concentrations nor the amount of oral consumption to 

all three NIS inhibitors are available to calculate or estimate the total NIS inhibition load (i.e., 

total goitrogen load) acting on the thyroid of non-nursing infants. 

The perchlorate exposure in non-nursing infants can be estimated using the results from 

the 2008 FDA Food Dietary Study. The 2008 FDA Food Dietary Study reports the total 

perchlorate intake from food for 6- to 11-month-old infants to be 0.26–0.29 μg/kg-day (i.e., not 

including potential perchlorate exposure from water) (Murray 2008, Table 5). Since the 

perchlorate RfD is 0.6 μg/kg-day, the perchlorate exposure from food for 6- to 11-month-old 

infants of 0.26–0.29 μg/kg-day represents 37% to 41% of the perchlorate RfD. This suggests a 

Relative Source Contribution (RSC) of about 60% for non-nursing infants. 

Unfortunately, this estimated perchlorate RSC is derived using a single chemical risk 

assessment process that is characterized as being outdated. In other words, limiting only 

perchlorate to protect public health does not insure that the total NIS inhibition load acting on the 

non-nursing infants is “safe” because the NIS inhibition exposure from thiocyanate and nitrate in 

the food and water of the non-nursing infant is not considered. The public health risk to nonnursing infants from a potentially excessive amount of NIS inhibitors is not known without 

knowing the non-nursing infants’ exposure to thiocyanate and nitrate. However, the relative 

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contribution of each NIS inhibitor to the total amount of NIS inhibition load acting on the body 

is known for adults. In typical nonsmoking U.S. adults, thiocyanate and nitrate from the 

consumption of food and water contributes the vast majority (i.e., > 99.9%) of the body’s total 

NIS inhibition load (see Section 7.2.1). Since a non-nursing infant’s diet contains the same food 

sources (e.g., vegetables (see Sections 3.3 and 3.4) that contribute thiocyanate and nitrate in an 

adult’s diet, the vast majority of the total NIS inhibition load acting on the thyroid of the nonnursing infant is still expected to be from thiocyanate and nitrate and not from perchlorate. 

Therefore, from a cumulative risk assessment standpoint, the majority of risk to non-nursing 

infants from exposure to NIS inhibitors is from thiocyanate and nitrate. Furthermore, to 

effectively characterize and manage the risk, the exposure to all three NIS inhibitors needs to be 

determined and the combined exposure needs to be managed to prevent an excessive total NIS 

inhibition load acting on the non-nursing infant. 

Another aspect of a cumulative risk assessment is that the body’s tolerance for NIS 

inhibition is a function of the amount of iodide in the diet. The lack of iodide is also an NIS 

stressor on the thyroid and also limits the amount of TIU by the thyroid. Therefore, within 

certain biological limits, the more iodide in the diet, the body can tolerate a larger total NIS 

inhibition load without adverse effects. The converse of this relationship is also true, within 

certain biological limits: the less iodide in the diet, the body cannot tolerate as much total NIS 

inhibition load before adverse effects are observed. In short, there is no single limit to the 

amount of total NIS inhibition the body can tolerate; the body’s toleration of NIS inhibition is on 

a sliding scale depending on the amount of iodide in the diet. 

In regard to the iodide nutrition observed in non-nursing infants, the iodide nutrition level 

can be estimated using the results from the 2008 FDA Food Dietary Study. The 2008 FDA Food 

Dietary Study identifies that baby foods and dairy products account for nearly all (90%) of the 

estimated iodine intake by infants. The 2008 FDA Food Dietary Study reports the range of 

estimated lower- and upper-bound average iodide intakes for 2003–2004 for 6- to 11-month-old 

infants to be 144-155 μg/day (Murray 2008, table 7). The 2008 FDA Food Dietary Study 

indicates that an adequate intake of iodide for 6- to 11-month-old infants is 130 μg/day (Murray 

2008, table 7). Therefore, the 2008 FDA Food Dietary Study indicates that the majority of 6- to 

11-month-old U.S. infants have an adequate intake of iodide, which allows these infants to 

tolerate a larger amount of total NIS inhibition load compared to an infant with an iodidedeficient diet. Unfortunately, the 2008 FDA Food Dietary Study was not designed to provide the 

iodide intake distribution within each population subgroup. This iodide intake distribution 

within the U.S. population subgroups would help to better characterize the public health risk 

because the risk to the public from NIS inhibitors increases with the decreasing intake of iodide. 

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8. Risk Characterization of NIS Stress 

In 2003, the EPA Framework for Cumulative Risk Assessment identifies, “For most 

exposure situations, hazard and dose response studies of all of the joint effects from the multiple 

stressors will not be available, so that conclusions will have to be based at least partly on the 

single stressor information” (EPA 2003, p 44). For perchlorate, a risk characterization cannot be 

done in humans because adverse health effects have not been clearly demonstrated in any human 

population exposed to perchlorate (NAS 2005, p 177). However, the EPA Framework for 

Cumulative Risk Assessment allows the risk characterization to be based on the adverse effects 

observed in one of the stressors, and then be applied to the joint effects from the multiple 

stressors. Therefore, the risk characterization for NIS stressors must be done by using an NIS 

stressor in which adverse effects in children born to mothers with low maternal TIU during 

pregnancy and nursing have been documented and reported. The excessive maternal exposure to 

the NIS stressor, the lack of iodide, is the principal NIS stressor in which adverse effects have 

been documented and reported in children born to mothers with low maternal TIU during 

pregnancy and nursing. Thus, the adverse effects from the lack of iodide stressor can be used to 

conduct the initial three steps in a risk characterization (i.e., hazard characterization, doseresponse assessment, and exposure assessment) to this public health issue. The exposure to the 

lack of iodide stressor that induces an adverse effect can be related back to the joint exposure 

level of all four NIS stressors by integrating the joint exposure into a single parameter or 

“common metric” (EPA 2003, p 55, section 3.3.3.1). The single parameter for measuring the 

NIS stress level is the TIU. The Tonacchera Model can be used to mathematically calculate the 

resulting TIU level from the concurrent joint exposure to all four NIS stressors. 

The inclusion of the lack of iodide stressor is essential in characterizing and 

understanding this public health issue. An insufficient uptake of iodide in both the pregnant 

mother’s thyroid and her child’s thyroid during gestation and lactation is the initiating biological 

event that triggers the subsequent potential for permanent brain damage in the developing fetus 

and nursing infant. An insufficient uptake of iodide can be caused by the exposure to an 

excessive amount of NIS inhibitors, but an insufficient uptake of iodide can also be caused by 

the lack of iodide in the diet (i.e., iodide deficiency). The excessive ingestion of NIS inhibitors 

or an iodide-deficient diet (or a combination of both) can lead to an insufficient uptake of iodide; 

therefore, excessive NIS inhibitors or the lack of iodide both initiate the same subsequent 

adverse effects. Thus, critical insight into this public health issue can be learned by studying the 

adverse effects observed in the children of iodide-deficient pregnant women. The adverse effects 

observed in the offspring of iodide-deficient pregnant women are the same adverse effects 

expected to be observed in the offspring of pregnant women with an excessive exposure to NIS 

inhibitors, because the two groups share the same mechanism of toxicity (i.e., a low TIU). 

The 1991 EPA Guidelines for Developmental Toxicity Risk Assessment clearly states that 

human studies are the most appropriate data for conducting developmental toxicity risk 

assessments (EPA 1991, p 1). Human data avoid the uncertainties of extrapolating from animals 

studies to humans. Human data also provide the ability to identify subtle mental deficits (e.g., 

ADHD or verbal comprehension) that are not possible to detect or identify in animal studies. 

Unfortunately, subtle adverse effects can be observed in the children born to iodide-deficient 

pregnant women. The type and severity of these adverse effects that occur in the children born 

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to iodide-deficient pregnant women can be studied and identified. Furthermore, through the use 

of the Tonacchera Model, the amount of TIU that results in adverse effects to the offspring can 

be calculated from the iodide exposure levels in the pregnant women. To accomplish this task, 

the lack of iodide stressor will be evaluated using the traditional risk assessment techniques of a 

hazard characterization, dose-response assessment, and an exposure assessment. 

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8.1 Hazard Characterization 

EPA’s Framework for Cumulative Risk Assessment states that a stressor does not have to 

be the exposure to a chemical, but the “absence of a necessity” (EPA 2003). In terms of the 

necessity for the thyroid to uptake enough iodide to make a sufficient supply thyroid hormones 

for proper brain development, the potential absence of iodide in the diet of pregnant women and 

neonates is the dominant stressor in this public health issue, according to the Tonacchera Model. 

To characterize the risk from this nonchemical NIS stressor, the same process used for chemical 

agents is appropriate, except this time the adverse health effects are observed by the lack of 

exposure. The hazard characterization is the description of the potential adverse health effects 

attributed to a specific environmental stressor; the mechanisms by which a stressor exerts its 

toxic effect; and the associated dose, route, duration, and timing of exposure (EPA 2002). 

The absence of iodide in the diet (i.e., poor iodide nutrition) acts through the same 

mechanism of toxicity as perchlorate and the other NIS inhibitors. Although the lack of iodide 

does not act as an NIS inhibitor, the lack of iodide has the same biological result by preventing 

an adequate uptake of iodide by the NIS. Therefore, the lack of iodide would have the same 

adverse health effects as proposed by an excess exposure to perchlorate. 

The EPA mode of action for perchlorate proposed a continuum of possible health effects 

from perchlorate exposure that included the potential for permanent neurodevelopmental deficits 

in infants (EPA 2002a). The NAS Committee mode of action for perchlorate also identifies a 

continuum of biological effects that includes the possibility for abnormal fetal and child growth 

and development (NAS 2005). However, the NAS Committee “emphasizes” that the inhibition 

of iodide uptake by the thyroid has been the only consistently documented effect of perchlorate 

exposure in humans (NAS 2005, p 165). The NAS Committee also states that the continuum of 

possible health effects is only proposed and has not been clearly demonstrated in any human 

population exposed to perchlorate (NAS 2005, p 165). Therefore, the potential perchlorate 

hazard for neurodevelomental deficits in infants is only theoretical. 

By contrast, the neurodevelopmental hazard from this nonchemical NIS stressor (i.e., the 

lack of iodide) is not theoretical. The neurodevelopmental hazard from this nonchemical NIS 

stressor is known, characterized, and observed in children born in iodide-deficient populations. 

Iodide deficiency is fundamental in the cause of endemic cretinism (Delange 2005a). Cretinism 

is the extreme, irreversible mental retardation and impairment of physical development of 

children. In severely iodide-deficient populations, the prevalence of cretinism can reach 5% to 

15% of the population. However, the combined effect of the four NIS stressors on the uptake of 

iodide by the thyroid does not reach this level of severity in the United States. 

The neurodevelopmental hazard from the lack of iodide is a not threshold effect, but is 

better characterized by a dose-response relationship. In other words, the severity of mental 

deficits and the frequency of occurrence of mental deficits increase with the severity of the 

iodide deficiency. One cross-sectional epidemiological study in children observed a doseresponse relationship between UIC and IQ, (i.e, IQ decreases with decreasing UIC) (SantiagoFernandez 2004). Children born and raised in mild iodide-deficient populations are not reported 

to have intellectual or cognitive deficits (Delange 2001), but are observed to have slower 

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reaction times (Lombardi 1995; Vitti 1992). However, children born and raised in moderate 

iodide-deficient populations have minor, subtle, or overt neurological, psychological, and 

intellectual deficits (Delange 2005, p 278; Lombardi 1995). These mental deficits are of the 

same nature but less prominent than the mental deficits found in children born in severe iodidedeficient populations. Brief thyroid failure during fetal development or infancy, when the brain 

is still developing, is thought to cause these mental deficits. 

In 1994, Bleichrodt conducted a meta-analysis of 18 studies comparing the mental 

development in children between either iodide-sufficient and iodide-deficient regions or iodide 

prophylaxis (iodide supplement) and a placebo (Bleichrodt 1994). Meta-analysis relies on the 

fact that statistical significance is highly dependent on sample size. By combining the results 

from 18 smaller studies, the meta-analysis generated a larger dataset – a total of 2,214 subjects – 

to identify a statistically significant trend. A meta-analysis generates a Cohen d-value where d is 

the difference between the two group means (i.e., control and experimental groups) divided by 

the standard deviation. A Cohen d-value of a d = 0.2 is classified as a small effect size, a d = 0.5 

is classified as a medium effect size, and a d = 0.8 is classified as a large effect size. The 

Bleichrodt meta-analysis of the effects of iodide deficiency on cognitive development found a 

large effect size with a d-value = 0.9. Therefore, the mean IQ scores between iodide-deficient 

group and the iodide-sufficient group were 0.9 SD or 13.5 IQ points apart. In other words, 82% 

of the children from the iodide-deficient group score below the average IQ score of a iodidesufficient child. 

The specific adverse mental deficits are documented to be observed in children born to 

mothers with mild iodide deficiency, moderate iodide deficiency, and hypothyroidism are 

provided in the following three sections. 

Adverse Effects Observed in Mild Iodide-Deficient Populations 

Lombardi 1995 Study: The Lombardi epidemiological study evaluating the 

neuropsychological impairment of mild iodide deficiency during fetal and neonatal life reported 

delayed reaction times in children aged 6-10 in Tuscany, Italy (Lombardi 1995). The study 

measured the reaction time between visual stimulus and the response for two child populations: 

a mildly iodide-deficient area (IDA) and an iodide-sufficient area (ISA). The measurement of 

simple reaction time is a sensitive test to detect subtle neurological damage from mild iodidedeficiency during fetal and neonatal brain development. The following table summaries the 

study: 

Village 

Number of 

Children 

Urinary Iodide Concentration 

(mean ± SD) Description of Iodide Level 

Borgo a Mozzano 719 80.1 ± 57 Iodide-Deficient Area (IDA) 

Marina di Pisa 106 173 ± 95 Iodide-Sufficient Area (ISA) 

Source: Lombardi 1995. 

Reaction time is known to decrease with age (i.e., explains the observed decrease in 

reaction time with age in this dataset, but the significance of the study is that reaction time of 

ISA children is statistically significantly shorter than the reaction time of the IDA children at 

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each age (p<0.05)). The following figure provides the observed reaction times between iodidedeficient and -sufficient children by year (note: the x-axis is age of the child in years): 

Vitti 1992 Study: The Vitti study also evaluated the neuropsychological impairment of 

mild iodide deficiency during fetal and neonatal life by measuring the reaction times in two 

groups of schoolchildren in Vagli, Italy (Vitti 1992). Group 1 contained 30 children (mean age 

11.5 years) who were born before iodide prophylaxis. Group 2 contained 27 children (mean age 

7.3 years) who were born after iodide prophylaxis. This study measured the reaction time 

between a visual stimulus and the response observed in the two groups and compared them 

against their age-matched controls living in an ISA. The results are summarized in the following 

table: 

Study Group 

Vagli Children 

Mean RT 

Aged-Matched 

Controls 

Mean RT* 

Statistical 

Significance 

Group 1 (mean age 11.5 yrs) 

(born before iodide prophylaxis) 355 msec 322 msec p < 0.05 

Group 2 (mean age 7.3 yrs) 

(born after iodide prophylaxis) 473 msec 442 msec 

Not statistically 

significant 

*RT – Retention Time 

Source: Vitti 1992, table 4. 

The Vitti paper discusses that the slower retention times observed in children born in 

mild IDAs are potentially not related to cognitive impairment, but might be related to slightly 

altered efficiency of the peripheral nerves to transmit a signal to and from the brain. 

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Santiago-Fernandez 2004 Study: The Santiago-Fernandez study evaluated the possible 

relationship between UIC (i.e., a surrogate for iodide intake) and the intellectual capacity 

observed in 1,221 schoolchildren in the province of Jaen in southeast Spain (Santiago-Fernandez 

2004). The mean ages of the children were 10.8 ± 2.9 yrs (range 6-16 years) and were from 1st, 

5th, and 8th grades. The IQ was determined by the Cattell’s g factor test. IQ is statistically 

lower in children with UIC <100 μg/L than children with UICs >100 μg/L. This observation is 

summarized in the following table: 

Urinary Iodide Concentration Intelligence Quotient Statistical Significance 

> 100 μg/L 99.03 ± 15.81 

p = 0.01 ≤ 100 μg/L 96.40 ± 17.46 

Source: Santiago-Fernandez 2004, table 2. 

The IQ level of children is associated with the type of salt consumed. In the United 

States, iodized salt contains about 100 parts per million (ppm) potassium iodide, which 

corresponds to 77 μg iodide per gram of salt (Dunn 1998). By contrast, both common salt and 

sea salt contain negligible amounts of iodide. As a result, iodized-salt-consuming children had 

the highest level of UIC of about 118 μg/L. The common-salt- and sea-salt-consuming children 

had a statistically lower level of UIC of about 99 μg/L and 94 μg/L, respectively. The IQ of the 

iodized-salt-consuming children with the higher iodide intake was about 101, while the IQs of 

the common-salt- and sea-salt-consuming children with lower iodide intake was statistically 

lower at about 97 and 96, respectively. These results are summarized in the following table: 

Type of Salt Consumed 

Iodide Content 

(μg iodide/g of salt) 

Urinary Iodide Conc. 

(μg/L) 

Intelligence 

Quotient 

Iodized [rock salt] 77 μg iodide/g of salt 118.22 ± 77.39a 100.63 ± 15.44c 

Common 

[noniodized rock salt] 0.7 μg iodide/g of salt* 99.48 ± 68.85b 96.64 ± 16.85d 

Marine 

[sea salt contains very little 

iodide] 1.4 μg iodide/g of sea salt** 94.44 ± 70.40b 95.50 ± 18.22d 

Statistical significance between a & b is p = 0.0004 

Statistical significance between c & d is p = 0.001 

Source: Santiago-Fernandez 2004, table 5; * Aquaron 2000; ** Fisher 1980. 

The IQ level of children is associated with the amount of milk consumed. Milk is known 

to be a significant source of iodide in the diet. As a result, children consuming milk 3 or more 

times a day have highest levels of UICs of about 119 μg/L, while the children consuming milk 2, 

1, or < 1 time(s) per day had a statistically lower level of UIC of about 99, 87, and 81 μg/L, 

respectively (see table below). The children consuming milk 3 or more times per day or 2 times 

per day have statistically higher IQs of about 99 and 100, respectively, than children consuming 

milk 1 or < 1 time per day, who had IQs of 94 and 94, respectively. These results are 

summarized in the following table: 

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Frequency of milk intake 

Urinary Iodide Conc. 

(μg/L) Intelligence Quotient 

3 times per day 118.60 ± 79.80a 98.01 ± 15.96c 

2 times per day 98.68 ± 68.70b 99.90 ± 16.23c 

1 time per day 87.10 ± 58.40b 93.64 ± 19.41d 

< 1 time per day 80.82 ± 48.60b 93.75 ± 16.93d 

Statistical significance between a & b is p = 0.0001 

Statistical significance between c & d is p = 0.0008 

Source: Santiago-Fernandez 2004, table 5. 

The UICs in the children of the Santiago-Fernandez study do not reflect the iodide 

nutritional status of the pregnant mother and do not attempt to measure any potential brain 

development issues during gestation. Furthermore, the Santiago-Fernandez study is not an 

interventional study to evaluate whether the observed effects on IQ are reversible if the UIC is 

increased in the low IQ children. 

The major contribution of the Santiago-Fernandez study was to document the sensitivity 

of the child’s thyroid to iodide intake and the resulting cognitive performance of the brain. 

Another major significant contribution of the Santiago-Fernandez study was to document that 

iodized salt and milk are significant sources of iodide. Milk is a significant source of iodide in 

children which is confirmed by the FDA TDS (Murray 2008). Likewise, while iodized salt 

contains 77 μg iodide/g of salt (Dunn 1998), noniodized salt and sea salt contain only about 0.7 

μg iodide/g of noniodized salt (Aquaron 2000) and about 1.4 μg iodide/g of sea salt (Fisher 

1980). Therefore, noniodized salt and sea salt do not provide a significant source of iodide in the 

diet, which results in a corresponding decrease in cognitive performance (Santiago-Fernandez 

2004, table 5). 

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Adverse Effects Observed in Moderate Iodide Deficient Populations 

Bleichrodt 1989 Study: A study evaluated the mental and psychomotor development 

effects on children of moderate iodide deficiency (Bleichrodt 1989). The study evaluated 162 

children aged 2 months to 12 years in an IDA in Spain having a mean urinary iodine of 45 ± 41 

μg/L. The control group consisted of 193 children aged 2 months to 12 years old in a non-IDA 

having a mean urinary iodine of 77 ± 46 μg/L. Both T4 and iodide urinary excretion levels were 

markedly lower in the iodide-deficient group. The mental development scores are significantly 

lower (p ≤ 0.01) across all three age groups (i.e., 0-2.5 years, 2.5-6 years, and 6-12 years). The 

mental development scores are summarized in the following table: 

Age Group 

Mental Development Scores 

Control Children Moderately Iodide Deficient Children 

0–2.5 yrs 108.1 ± 16.0 95.9 ± 16.3 

2.5–6 yrs 105.1 ± 11.6 88.1 ± 15.0 

6–12 yrs 101.6 ± 13.1 88.0 ± 12.7 

Source: Bleichrodt 1989, table 3. 

The moderately iodide-deficient group was subsequently treated twice with 2 ml of 

Lipiodol orally to correct its iodide deficiency and was retested 32 months later. However, the 

average mental developmental scores and distribution between the moderately iodide-deficient 

group and the group after having been treated are nearly similar (i.e., mean scores of 90.2 and 

88.0 respectively). This observation is consistent with the belief that the mental deficit was 

irreversible and occurred during fetal and neonatal development and is not a temporary side 

effect of iodide deficiency. The distribution of mental development scores for the three age 

groups (0-2.5 years, 2.5-6 years, and 6-12 years) are provided below: 

Source: Bleichrodt 1989, figure 2. 

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Source: Bleichrodt 1989, figure 3. 

Source: Bleichrodt 1989, figure 4. 

The Bleichrodt study also evaluated the psychomotor development of the 6- to 12-yearolds. The study found the coordination of body movements to be similar between the two 

groups, but the iodide-deficient children scored significantly lower (p ≤ 0.01) in manual dexterity 

and speed of reaction. The moderately iodide-deficient group was subsequently treated twice 

with 2 ml of Lipiodol orally to correct their iodide deficiency and retested 32 months later. 

However, the average scores and distribution of scores between the moderately iodide-deficient 

group and the group after having been treated are nearly identical. This observation is consistent 

belief that the mental deficit was irreversible and occurred during fetal and neonatal development 

and is not a temporary side effect of iodide deficiency. The distribution of scores for manual 

dexterity, speed of reaction, and coordination of movements are provided below: 

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Source: Bleichrodt 1989, figure 7. 

Source: Bleichrodt 1989, figure 8. 

Source: Bleichrodt 1989, figure 9. 

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Vermiglio 2004 Study: The Vermiglio 2004 prospective study evaluated the 

neuropsychological development of 16 children born to 16 healthy mothers living in a 

moderately IDA (Area A) and compared them against 11 control children born to 11 agematched women in a marginally sufficient iodide area (Area B). The urinary iodide excretion 

level in Area A during pregnancy was 48.1 ± 38.2 μg/day. The urinary iodide excretion level in 

Area B during pregnancy was 95.2 ± 55.8 μg/day. All children from both Areas A and B were 

euthyroid at neonatal screening, at the first examination (18-36 months), and at the second 

examination (8-10 years). 

In 2001-2002, at the age of 8-10 years, the children were evaluated for ADHD and their 

intelligence was tested. In the moderately IDA A, 11 of 16 (68.7%) children had ADHD. Of the 

11 ADHD children, 5 had combined-type ADHD subtype, 5 had the predominantly hyperactiveimpulsive-type ADHD subtype, and 1 child had predominantly inattentive-type ADHD subtype. 

None of the control children from Area B had ADHD. 

The Wechsler Intelligence Scale for Children (WISC)-III full-scale IQ scores, and 

subscale scores for ADHD-positive children from Area A, the ADHD-negative children from 

Area A, and the control children in Area B are summarized below: 

Source: Vermiglio 2004, table 2. 

The intelligence WISC-III full scale IQ scores of 88.0 ± 6.9 for the ADHD-positive 

children from Area A were statistically lower than the corresponding IQ scores of 110 ± 10 

control children from Area B. Of the 15 subscale scores, the following 9 subscale scores of the 

ADHD-positive children from Area A were found to be statistically lower than the 

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corresponding scores in the control children from Area B: WISC-III freedom-fromdistractibility score, WISC-III verbal IQ score, WISC-III verbal section tests (general 

comprehension, arithmetic, similarities, vocabulary), WISC-III performance IQ score, and 

WISC-III performance section tests (picture completion and mazes). 

The free T4 level and TSH level of the pregnant women at weeks 8, 13, and 20 for the 

three groups (ADHD positive from Area A, ADHD negative from Area A, and controls from 

Area B) are provided below: 

Source: Vermiglio 2004, figure 2. 

Figure 2 shows that 8 of 16 (50%) pregnant women from the moderately IDA A and 1 of 

11 (9.1%) pregnant women from the marginally ISA B (i.e, UIC of 95 μg/L is actually 

considered mildly iodide deficient) had thyroid failure in early pregnancy in the form of 

hypothyroxinemia. The term hypothyroxinemia is used to describe pregnant women with normal 

TSH concentrations (0.4 – 4.0 uU/ml), but have low serum fT4 values as compared with the 

range values calculated (mean ± 2 SD) at the same stage of pregnancy (8, 13, and 20 weeks) in a 

series of 50 healthy women with moderately adequate iodide intake (150–200 μg/day). 

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Vermiglio stated that ADHD is a developmental disorder involving difficulties with 

sustained attention, distractibility, poor impulse control, and hyperactivity or inability to regulate 

activity level to situational demands (Vermiglio 2004). The disorder is believed to arise early in 

childhood (3-7 years) and is considered organic in pathology. The current view is that 

dysfunctions of both the frontal and prefrontal lobes, involved in impulsivity and motor activity 

control, and of cortical and subcortical activity areas, involved in inhibition of irrelevant 

responses and executive function, are responsible for the disorder. 

ADHD is a common behavioral disorder among children. The estimated occurrence of 

ADHD at 19 years of age is 7.5% (6.5%-8.4% at a 95% confidence interval (CI)) (Barbaresi 

2004). A high prevalence ADHD (70%) is reported in children with generalized resistance to 

thyroid hormone (GRTH). GRTH is a disease caused by mutations in the thyroid receptor-β

gene, which reduces the response of tissues to thyroid hormone (i.e., the developing fetal nerve 

cells do not get enough signal from the thyroid hormone to develop properly). Since the ADHD 

prevalence in the Vermiglio study was 69% in the moderately iodide-deficient and 87.5% in 

hypothyroxinemic, it suggests that a decreased signal through the thyroid receptor-β (i.e., by a 

mutated thyroid receptor-β gene, decreased maternal supply of T4 to the fetus during the first 20 

weeks caused by iodide deficiency, or a combination of both) is associated with ADHD. The 

Vermiglio study suggests that the rates of ADHD could be significantly reduced by preventing 

iodide deficiency during pregnancy. Furthermore, the Vermiglio study suggests the possibility 

that providing a normal thyroid hormone level during gestation may allow a child with GRTH to 

have normal brain development by not challenging the mutated thyroid receptor-β gene. 

The Vermiglio 2004 study is one of four studies reporting that maternal hypothyroxinemia 

during early pregnancy results in neurodevelopmental deficits in children (Kooistra 2006). 

Hypothyroxinemia is a common condition in pregnant women characterized by low maternal fT4 

levels with normal TSH levels (Kooistra 2006). Hypothyroxinemia is regarded to be without 

consequences for the mother and fetus (Kooistra 2006). Hypothyroxinemia reflects a condition in 

which the pregnant mother has difficulty meeting her own T4 needs and is unable to meet the fetal 

demand for T4 for proper brain development (Kooistra 2006). Fetal hypothyroxinemia is induced 

by iodide deficiency because the immature fetal thyroid is unable to increase its avidity for iodide 

despite up-regulation of NIS expression in the fetal thyroid and placenta during iodide deficiency 

(Delange 2005a). The increased iodide clearance rate will further decrease the iodine stores of the 

fetal thyroid and decrease fetal T4 synthesis (Delange 2005a). The transfer of maternal T3 does not 

protect the fetal brain. The pregnant woman transfers maternal T4 until birth, at which time 

maternal T4 represents 20% to 50% of the cord serum T4. Therefore, the fetal thyroid is required 

to provide the major T4 during the last half of pregnancy when the fetal thyroid is unable to adapt 

to a decreased supply of iodide caused by its mother’s iodide deficiency. In rats, the fetus can 

compensate for hypothyroxinemia by increasing the fetal brain deiodinase type 2 activity, which 

helps protects the fetal brain from T3 deficiency (Delange 2005a). 

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Fenzi 1990 Study: A neuropsychological assessment in school-aged children in an area 

of moderate iodide deficiency found minor impairment of perception, motor, and attentive 

functions (Fenzi 1990). The epidemiological study evaluated 384 schoolchildren ages 6-14 years 

in eastern Tuscany having a mean urinary iodine excretion of 39 ± 38 μg/g creatinine. The 

control group consisted of 352 sex- and age-matched schoolchildren from an ISA with a mean 

urinary iodine excretion of 88 ± 15 μg/g creatinine. The tT4, tT3, and TSH levels were within the 

normal range for both groups. The study failed to show major differences in the global 

neuropsychological performance and cognitive performance between the two groups. However, 

significant differences were observed in subtest for information, verbal, and coding tests that 

were administered to the third graders. The lower scores in the information and verbal subtests 

resulted in a lower verbal IQ for the third grader in the moderately IDA. Furthermore, the lower 

score on the coding test, which is less correlated with global cognitive abilities, suggests minor 

impairment in perception, motor, and attentive functions. 

Vermiglio 1990 Study: In the Vermiglio 1990 study, the visual perceptual integrative 

motor ability was investigated in 719 6- to 12-year-olds living in two moderately IDAs in Sicily, 

Italy. A modified Bender-Gestalt test was administered to all 6- to 12-year-old children. The 

test consists of copying as accurately as possible a number of geometrical figures, explores 

visual perceptive and neuromotor manual ability, and is affected by specific segments of 

intellectual function (i.e., memory, spatial concepts, and ability to organize and represent). The 

children in the moderately deficient areas scored statistically worse on the Bender-Gestalt test 

than the children in the iodide-sufficient control area. The results are summarized in the 

following table: 

Performance on 

Bender-Gestalt Test 

Moderately IodideDeficient Areas A + B 

(number of children) 

Iodide-Sufficient 

Control Area C 

(number of children) 

Statistical 

Significance 

(χ2

 method) 

Defective 99 (13.8%) 13 (3.5%) P < 0.000001 

Borderline 124 (17.2%) 14 (3.8%) P < 0.000001 

Nondefective 496 (69.0%) 343 (92.7%) P < 0.0000005 

Source: Vermiglio 1990, table 3. 

A Terman-Merrill test was administered to 96 of the 99 defective children and 62 of the 

124 borderline children found on the Bender-Gestalt test in the moderately IDAs A + B. The 

Terman-Merrill test evaluates general intellectual aptitude. Intellectual aptitude deficiencies 

appeared in the following segments listed in decreasing percentage order of involvement: 

vocabulary (40%), logical and critical capacities (32%), reading abilities (30%), calculating 

abilities (28%), handwriting (25%), memory (20%), and comprehension (15%). Of the 96 

defective children tested, 91 (i.e., 94.8%) had IQ scores less then 90% on the Terman-Merrill 

test. Of the 62 borderline children tested, 35 (i.e., 56.4%) had IQ scores less then 90% on the 

Terman-Merrill test. The results from the Terman-Merrill test are summarized below: 

Performance on the Intelligence Quotient Score on the Terman-Merrill Test 

Bender-Gastalt Test <90 90-95 96-100 

Defective (n = 96) 91 (94.8%) 5 0 

Borderline (n = 62) 35 (56.4%) 23 4 

Nondefective (n = 12) 0 10 2 

Source: Vermiglio 1990, table 4. 

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Adverse Health Effects Observed in Children of Hypothyroid Pregnant Mothers 

A 1999 maternal thyroid deficiency study reported on the subsequent neuropsychological 

development of the children born to hypothyroid mothers (Haddow 1999). The study identified 

47 pregnant women with subclinical hypothyroidism having elevated TSH (i.e., > 6 ul/ml) and 

normal T4 levels. The study also identified another 15 pregnant women with overt 

hypothyroidism having both elevated TSH and low T4 levels. A survey of pregnant women in 

the United States identified that 2.5% of pregnant U.S. women have hypothyroidism (Utiger 

1999). Likewise, North American and European evaluations identify that up to 0.5% of pregnant 

women (1 in 200) may have overt hypothyroidism and up to 2.5% of women (1 in 40) have 

undetected subclinical hypothyroidism before pregnancy (Morreale de Escobar 2004, p U33). 

Since hypothyroidism is difficult to diagnose, the median time to a hypothyroid diagnosis in 

women is 5 years (Haddow 1999). 

Of the 48 pregnant women that did not receive treatment for their thyroid deficiency, the 

full-scale IQ of their children averaged 7 points lower (p = 0.005) than the 124 matched control 

children. The children from the 48 untreated pregnant women had statistically poorer 

performance on the following nine neuropsychological tests: 

WISC-III full-scale IQ score (Intelligence Test) 

Number of children with IQ score ≤ 85 (Intelligence Test) 

WISC-III freedom-from-distractibility score (Attention Test) 

Continuous Performance Test score > 8% (Attention Test) 

Word Discrimination (Language Test) 

WISC-III verbal IQ score (Language Test) 

PIAT-R* reading-recognition score (School Performance Test) 

WISC-III performance IQ score (Visual-motor performance) 

Pegboard-test score (Nondominant hand) (Visual-motor performance) 

*(PIAT-R) stands for Peabody Individual Achievement Score – Revised 

The performance results on all 15 neuropsychological tests were observed to be lower for 

the untreated children than the control children. However, the statistical significant of this trend 

was not evaluated. 

The children of the 14 treated pregnant women had performance results on 13 of the 15 

neuropsychological tests that were comparable to the control children. However, the study did 

not conduct a statistical comparison between the children of the treated pregnant women with 

hypothyroidism and the control children (i.e., to determine how effective the treatment was). 

Even after treatment, the results of the children of the 14 treated pregnant women were worse 

than both the control and untreated children on the following two tests: Continuous Performance 

Test (Attention Test) and School difficulties and learning problems (School Performance Test). 

The performance results for all 15 neuropsychological tests for the children of both the treated 

and untreated pregnant women are provided below: 

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Source: Haddow 1999, p 554, table 4. 

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8.2 Dose-Response Assessment 

A dose-response assessment is defined as “a determination of the relationship between 

the magnitude of an administered, applied, or internal dose and a specific biological response. 

Response can be expressed as measured or observed incidence, or change in level of response, 

percent response in groups of subjects (or population), or the probability of occurrence or change 

in level of response within a population” (IRIS 2006, EPA 2002). 

Ideally, one would like to know the internal dose of free iodide concentration in the blood 

serum in contact interacting with the NIS to establish the dose. However, determining an 

internal dose of free iodide in the blood serum is problematic. Healthy levels of inorganic iodide 

concentrations in serum are very minute and are about 1 pg/dL (Demers 2003, p 77). Due to the 

difficulty in measuring plasma inorganic iodide (PII) concentration, the measurement of PII is 

limited to research studies in pregnancy. Since about 90% of ingested iodide is excreted in the 

urine, the median urinary concentration is the most practical measurement of iodide intake in a 

population (Dunn 1998). Therefore, in most epidemiological studies, the UIC is used as a 

surrogate for iodide intake. 

The observed biological responses for iodide is inversely proportional to dose (i.e., the 

more you have in your diet, the less adverse effects that are observed). The dose-response curve 

for iodide is summarized in the following table: 

Observed Biological Response 

Iodide 

Sufficient 

Mild 

Iodide 

Deficiency 

Moderate 

Iodide 

Deficiency 

Severe 

Iodide 

Deficiency 

Median UIC (μg/L) in school-aged 

children and adults 

(UIC is a surrogate measurement for 

iodide intake (i.e., dose)) 100 to 200 99 to 50 49 to 20 < 20 

Prevalence of goiter (%) 

in school-aged children 

(Goiter Grades > 0) < 5.0 5.0–19.9 20.0–29.9 ≥ 30 

Frequency of thyroid volume (%) in 

school-aged children 

(>97th percentile by ultrasound) < 5.0 5.0–19.9 20.0–29.9 ≥ 30 

Frequency of elevated serum TSH in 

newborns (%) 

(> 5 mU/L whole blood) ≤ 3.0 3.0–19.9 20.0–39.9 ≥ 40 

Source: Delange 1998. 

The frequency of the following biological responses are observed to increase with the the 

lack of iodide (i.e., decreasing iodide dose): goiter in school-aged children, frequency of thyroid 

volume >97th in school-aged children, and elevated TSH levels in newborns. This pattern of 

response to the lack of iodide shows that a segment of the population is more sensitive (i.e., 

thyroid-sensitive population) than the rest of the population. In ISAs (i.e., little to no thyroid 

stress), the baseline frequency is that up to 5% of school-aged children have goiter and up to 3% 

of newborns have elevated TSH. By comparison, in the minimal thyroid stress population 

induced by mild iodide deficiency, the frequency goiter in school-aged children increases to up 

to 19.9% and the frequency of elevated TSH in newborns increases to up to 19.9%. In other 

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words, at least 80% of the newborns are unaffected by mild iodide deficiency, while up to 20% 

are adversely impacted (i.e., a heterogenous response is observesed in the population). Likewise, 

in the considerable thyroid stress population induced by moderate iodide deficiency, the 

frequency goiter in school-aged children increases to up to 29.9% and the frequency of elevated 

TSH in newborns increases to up to 39.9%. In other words, at least 60% of the newborns are 

unaffected by moderate iodide deficiency, while up to 40% are adversely impacted (i.e., a 

heterogenous response is observesed in the population). Furthermore, even in severe IDA, not 

everyone gets goiter nor does everyone have cretins. For example, in seven severe iodidedeficient cities, the percentage of elevated TSH in newborns did not reach 100% but ranged from 

47% in Osh, Kyrgyzstan, to 80% in Lahore, Paskistan, in relation to the severity of the iodide 

deficiency (Sullivan 1996). In summary, the biological response to iodide deficiency is not 

uniform across the human population and has to be taken into account in a cumulative risk 

assessment. 

This observation (i.e., not all individuals develop goiters or elevated TSH levels in IDAs) 

indicates a heterogeneous level of adaptability to iodide deficiency within the human population. 

A genetic modeling study supports this observation. In euthyroid subjects, quantitative genetic 

modeling calculated that genetic factors account for 71% (61-78%, CI 95%) of the individual 

differences in thyroid volume, where as the estimate for unique environmental effects account 

for only 29% (22-39%, CI 95%) (Hansen 2004). Therefore, the iodide-sensitive thyroid 

population should be added to the list of sensitive groups for this public health issue. The iodidesensitive thyroid population is not a trivial concern (e.g., such as an unexplained rare 

idiosyncratic reaction), because elevated TSH in neonates occurs up to 17% in the mild iodidedeficient population (i.e., 19.9% – 3% background) and up to 37% in the moderately iodidedeficient population (i.e., 39.9% - 3% background). Therefore, neonates have elevated serum 

TSH more frequently than adults for the same level of iodide deficiency (Delange 1998). Thus, 

neonates appear hypersensitive to iodide deficiency. Thus, the most sensitive population for 

cumulative risk assessment purposes is the iodide-sensitive fetus and neonate during gestation 

and lactation whose mothers are iodide deficient. 

Since the early 1970s, newborns are screened for permanent congenital hypothyroidism 

(CH) (incidence of CH is about 1 in 4,000 births) by measuring the serum TSH (Delange 1998). 

However, CH screening also detects transient primary hypothyroidism (incidence can be as high 

as 1 in 10 neonates). Neonatal TSH screening is one of the indicators recommended by the 

World Health Organization (WHO), the United Nations International Children’s Emergency 

Fund (UNICEF), and the International Council for the Control of Iodine Deficiency Disorders 

(ICCIDD) for assessing iodide deficiency disorders and their control (Delange 1998). Neonatal 

TSH is the single indicator that focuses on potential brain damage, which is the major impact of 

iodide deficiency (Delange 1998). Neonates with elevated TSH levels are at a high risk of 

developing subclinical hypothyroidism in infancy and early childhood (Delange 1998). 

The Calaciura 2002 study evaluated 56 children with transient neonatal subclinical 

hypothyroidism at the neonatal TSH screening (Calaciura 2002). All 56 children had a TSH > 

20 mU/L at the initial neonatal screening, but during the recall/confirmation examination at 22.2 

± 6.2 days, 33 children (Group I) had a normal fT4 level and fully normal TSH level (i.e., < 5.0 

mU/L) and the remaining 23 children (Group II) had a normal fT4 level with high normal/slightly 

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elevated TSH level (i.e., 5-17 mU/L) (Calaciura 2002). Upon follow-up examination in early 

childhood, 70% of Group I children and 36% of Group II children had mild thyroid dysfunction. 

Calaciura determined that all infants with elevated TSH at neonatal screening are at risk for 

developing subclinical hypothyroidism in early childhood (odds ratio 44.6%; 95% CI 38.8­

50.4%). Furthermore, for the first time, several different thyroid abnormalities were identified in 

neonates with elevated TSH levels at birth. Twenty-four of the 56 children had one or more of 

the following thyroid abnormalities: genetic, immunological, and morphological. This 

observation documents a partially dysfunctional or underperforming thyroid in a subset of the 

human population that makes them more sensitive to NIS stressors (e.g., lack of iodide). The 

adaptability of the thyroid to respond to stress is not uniform in the human population and, 

therefore, should be thought of as being heterogeneous in the human population. The cumulative 

risk assessment has to incorporate this difference in the thyroid’s adaptability within the human 

population. 

Cognitive deficits in the children of mildly iodide-deficient pregnant women have not 

been documented (Delange 2001). Unfortunately, these epidemiological studies only compare 

children from a mild IDA against control children in an ISA. However, the human thyroid’s 

ability to compensate for mild iodide deficiency is not uniform across the population. Up to 17% 

of humans who may have partially dysfunctional thyroids with limited adaptability have 

difficulty compensating for mild iodide deficiency. Since neonatal TSH level is the single 

indicator that focuses on potential brain damage, the partially dysfunctional thyroid subgroup can 

be tentatively identified by grouping the neonates with an elevated TSH level. The current 

epidemiological studies evaluating the cognitive performance of children of mildly iodidedeficient pregnant mothers do not segregate the neonates with elevated TSH who are at greater 

risk of developing mental deficits for evaluation. The potential for lower cognitive performance 

in these elevated TSH neonates, averaging 8.5% (i.e., 17% ÷ 2) of the population in mild IDAs, 

is potentially lost in the average cognitive score of the school-aged children (i.e., the cognitive 

scores from the 91.5% of the normal TSH neonates statistically overwhelms the scores of the 

8.5% neonates with elevated TSH). Therefore, in order to confirm that a mild iodide deficiency 

in pregnant women does not cause any cognitive deficits in partially dysfunction thyroid 

fetuses/neonates (i.e., a potential sensitive group), the cognitive scores of children who had an 

elevated TSH level at birth need to be compared to the cognitive scores of appropriate controls 

(i.e., cognitive scores of children from ISAs or cognitive scores of children from mildly IDAs 

with normal TSH levels at birth). Therefore, in short, current epidemiological studies have not 

ruled out the possibility that cognitive deficits could be observed in fetuses/neonates with 

partially dyfunctional thyroids. 

The adverse effect of concern for this public health issue is the potential for mental 

deficits in fetuses and neonates. The dose-response relationship for mental deficits from the lack 

of iodide is characterized by the epidemiological studies identified in the hazard characterization 

assessment. These studies are primarily designed to identify and detect mental deficits. They 

were not specifically designed to establish a well-documented dose-response curve showing an 

increased occurrence of mental defects with decreasing dose of iodide. However, these studies 

show, as required by the definition of a dose-response assessment, a “change in level of 

response” with decreasing dose of iodide (i.e., a decreasing maternal TIU). The severity of the 

mental deficits clearly increases as the lack of iodide increases (i.e., as the maternal TIU 

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becomes lower). The following table summarizes the observed mental deficits in the children of 

mothers living in IDAs: 

Iodide Exposure Levels 

in Pregnant Women 

Observed Mental Deficits in the 

Children of Mothers in Iodide-Deficient Areas 

Iodide sufficient No increased occurrence of mental or physical effects 

Mild iodide deficiency 

Delayed reaction time 

Potential cognitive effects in partially dysfunctional thyroid 

 individuals (see discussion above) 

Increased frequency of mild thyroid dysfunction in childhood 

Moderate iodide deficiency 

Subtle, minor, or overt neurological, psychological, and intellectual 

deficits 

Severe iodide deficiency 

Cretinism 5–15% prevalence 

(severe, permanent mental and physical defects) 

Source: OIG Analysis. 

The NAS Committee concluded the first adverse effect in its mode-of-action model is 

hypothyroidism and any effects downstream (e.g., neurodevelopmental deficits in infants) of 

hypothyroidism clearly would be adverse (NAS 2005, p 166). The NAS Committee stated that 

“developmental deficits” are clinical manifestations of hypothyroidism (NAS 2005, p 29). The 

NAS Committee identifies hypothyroidism as a deficiency in thyroid hormone production (NAS 

2005, p 35). Overt (i.e., primary) hypothyroidism is indicated by high serum TSH 

concentrations and low T4 (Ladenson 2005). Mild hypothyroidism is indicated by elevated TSH 

and normal T4 (Ladenson 2005). The NAS Committee stated that: 

Iodide can be obtained only by ingestion of food or water that contains it. 

Therefore, iodide deficiency and reduction in thyroid hormone production 

can occur if iodide intake is very low. Because the body maintains the 

serum concentrations of thyroid hormones with narrow limits through 

feedback control mechanisms, there is remarkable compensation for 

iodide deficiency. Generally, thyroid production is normal even when 

iodide intake is quite low. Hypothyroidism occurs only if daily iodide 

intake is below about 10 to 20 μg (about one-fifth to one-tenth of the 

average intake in the United States) [10-20 μg of iodide intake equates to 

severe iodide deficiency]. However, in pregnant women, iodide 

deficiency of that severity can result in major neurodevelopmental deficits 

and goiter in their offspring. Lesser degrees of iodide deficiency may also 

cause important neurodevelopmental deficits in infants and children (NAS 

2005, p 6). 

The NAS Committee also states: 

Furthermore, among people 15-44 years old, including pregnant women, 

there are no differences in serum TSH and T4 concentrations between 

those with urinary iodide values less than 50 μg/L and those with higher 

values . . . ” (NAS 2005, p 46-47). 

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These statements represent the NAS Committee’s position that neurodevelopmental 

deficits in infants would not be expected to occur until severe iodide deficiency during 

pregnancy induces overt hypothyroidism in the mother, resulting in an elevated TSH 

concentration accompanied by a low T4. 

Unfortunately, the NAS Committee’s proposed mode-of-action model for perchlorate is 

not completely correct. The NAS Committee identifies that adults with moderate iodide 

deficiency have normal TSH and T4 levels (NAS 2005, p 48). The NAS adverse effect 

continuum presumes that pregnant women have to become hypothyroid before 

neurodevelopmental deficits are observed. However, this statement is not true. For example, 

due to the added stress of pregnancy, moderately iodide-deficient pregnant women are observed 

to develop hypothyroxinemia (i.e., normal TSH and low fT4). The hypothyroxinemia in 

moderately iodide-deficient pregnant women resulted in mental deficits of their children 

(Vermiglio 2004, figure 2). Furthermore, under mild iodide deficiency during pregnancy, the 

maternal thyroid function at delivery is characterized by “relative hypothyroxinemia,” which is 

an increased T3/T4 ratio (i.e., indicating a preference for T3 secretion) and slightly increased TSH 

levels (i.e., 97% of the pregnant women were still in the normal range) (Glinoer 1992). 

Likewise, the less-stressed state of mildly iodide-deficient pregnant women are be observed to be 

euthyroid (Glinoer 1995, figure 4), but they are documented to have children with permanent 

delayed reaction times (Lombardi 1995; Vitti 1992) and are documented to have up to a 17% 

increased occurrence of newborns with elevated TSH levels (i.e., subclinical hypothyroidism) 

over background levels observed in iodide-sufficient populations (Delange 1998). Therefore, 

pregnant women do not have to develop overt hypothyroidism, as proposed by the NAS 

Committee, to increase the risk of their offspring developing mental deficits. 

Although the maternal hypothalamic-pituitary-thyroid axis has a large ability to adapt to 

the stress from iodide deficiency without showing obvious changes in TSH and T4 levels (Soldin 

2005, p 184, figures 2 and 3), the fetal thyroid is immature and less able than the mother’s 

thyroid to adapt to the stress induced by mild or moderate iodide deficiency. Fetuses and 

neonates do not have a thyroidal store of hormones and have a proportionally higher demand for 

thyroid hormones because they use them for both development and homeostasis, while adults use 

thyroid hormones primarily for homeostasis only. During the third trimester, the fetal thyroid 

provides the majority of T4 (i.e., maternal T4 represents 20% to 50% of the cord serum T4) 

(Delange 2005a). Under iodide-deficient conditions, the immature fetal thyroid is unable to 

increase its avidity for iodide despite up-regulation of NIS expression in the fetal thyroid and 

placenta during iodide deficiency (Delange 2005a). The increased iodide clearance rate will 

further decrease the iodine stores of the fetal thyroid and decrease fetal T4 synthesis (Delange 

2005a). Fetuses and neonates appear to be more sensitive to iodide deficiency than pregnant 

women (Delange 1998). For mild to moderate iodide deficiency, maternal measurements of 

TSH, fT4, and T4 are not appropriate markers to identify thyroid stress from iodide deficiency 

(Soldin 2005, p 184). Thyroid function tests are not a measure of iodide sufficiency (Soldin 

2005, p 184). Therefore, maternal urinary iodide is the only marker known that can serve as an 

indirect measure of the amount of fetal thyroid stress induced by maternal mild to moderate 

iodide deficiency (Soldin 2005, p 184). 

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During mild and moderate iodide deficiency, the fetus has some ability to adapt to a decreased T4 

hormone supply by increasing the fetal brain type 2 deiodinase (D2) activity, which protects the 

fetal brain from T3 deficiency (Delange 2005a, p 737). The compensation mechanism is 

observed in tracer studies of neonatal rat brains (Bianco 2005, p 123). The increased production 

of T3 from T4 by the increased activity of fetal rat brain type 2 deiodinase and the prolonged 

residence time of T4 by the increased activity of fetal rat brain type 3 deiodinase (D3) mitigates 

the effects from severe iodide deficiency and mild to moderate hypothyroidism (Bianco 2005, 

p 123). The activation of this fetal rat brain D2-D3 deiodinase compensatory mechanism clearly 

indicates that the fetal rat brain is not getting an adequate supply of T4 during severe iodide 

deficiency and mild to moderate hypothyroidism. 

In summary, although the pregnant woman is often euthyroid during iodide deficiency, 

the fetal thyroid is less able to adapt to this iodide deficiency, resulting in the increased risk for 

fetal brain damage even though the mother’s thyroid hormone level remains normal. Thyroid 

function tests are not a measure of iodide sufficiency (Soldin 2005, p 184). Therefore, maternal 

urinary iodide is the only marker known that can serve as an indirect measure of the amount of 

fetal thyroid stress induced by maternal mild to moderate iodide deficiency (Soldin 2005, p 184). 

The lowest UIC level in pregnant women in which an adverse effect (e.g., delayed reaction time) 

is observed in the fetus is about 100 μg/L, which corresponds to a mild iodide deficiency. 

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8.3 Exposure Assessment 

An exposure assessment is defined as “an identification and evaluation of the human 

population exposed to a toxic agent [i.e., stressor in cumulative risk assessment terms], 

describing its composition and size, as well as the type, magnitude, frequency, route, and 

duration of exposure” (EPA 2002). 

As the background exposure levels to perchlorate, thiocyanate, and nitrate must be 

determined to conduct a cumulative risk assessment, the background exposure level to the lack 

of iodide (i.e., the iodide nutritional status) also needs to be known. As the dose-exposure 

assessment has identified the iodide levels at which various adverse effects occur, the exposure 

assessment determines the portion of the population that is exposed at these levels. Since 

neurological, psychological, and intellectual deficits are known to occur in moderately iodidedeficient populations, the exposure assessment needs to determine the size of the U.S. pregnant 

women subpopulation that might be moderately iodide deficient. Furthermore, since delayed 

reaction times and the possibly of cognitive deficits in partially dysfunctional thyroid individuals 

occur in mildly iodide-deficient populations, the exposure assessment must determine the size of 

the U.S. pregnant women subpopulation that might be mildly iodide deficient. 

U.S. Iodide Nutritional Status 

CDC’s National Center for Health Statistics (NCHS) surveyed the iodide levels in the 

U.S. population through NHANES. NHANES is designed to collect data on the health and 

nutritional status of a statistically representative sample of the U.S. population. According to 

WHO, iodide-sufficient populations have median UIC greater than 100 μg/L, and no more than 

20% of the population should have a UIC below 50 μg/L (Hollowell 1998). Although the 

median urinary levels in the U.S. population are adequate by the WHO definition, the median 

UIC has decreased more than 50% from NHANES I (1971-1974) to NHANES III (1988-1994), 

and remained at this lower value in NHANES 2000 (see table below). The decrease in iodide 

consumption since 1984 is thought to be due to the reduction in the amount of iodide in milk and 

the replacement of iodide salts by bromine salts as the dough conditioner in commercial bread 

production (Hollowell 1998). 

Population Group 

Urinary Iodide Levels (μg/L) 

NHANES I 

(1971-1974) 

NHANES III 

(1988-1991) NHANES 2000 

U.S. Population 

(6-74 years of age) 320 ± 6 μg/L 145 ± 3 μg/L 161 ± 7 μg/L 

Source: CDC/NCHS 2007. 

The NHANES 2000 median urinary iodide level of 161 μg/L (95% CI 14.7 – 17.6) agrees 

with the NHANES III median of 145 μg/L. However, the NHANES 2000 urinary iodide data 

represent only 1433 samples, which does not allow for detailed analysis of the iodide status of 

subpopulations (e.g., pregnant or lactating women). Since the NHANES 2000 median agrees 

with the NHANES III median, the NHANES III distribution data (i.e., the best available dataset) 

are used to assess the amount of the U.S. population, and the amount of the sensitive pregnant 

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and lactating population, with inadequate iodide. The following table summarizes the 

distribution of urinary iodide values determined in the NHANES III survey: 

Population Group 

Urinary Iodide 

Concentration 

Mean (SEM) 

Percentiles for Urinary Iodide (μg/L) from NHANES III 

(1988-1994) 

5th 10th 25th 50th (Median) 

U.S Population 

(ages 6-71+) 

(n = 21,298) 275 μg/L (27) 30 μg/L 45 μg/L 81 μg/L 145 μg/L 

Pregnant (n = 343) 196 μg/L (11) 43 μg/L* 58 μg/L 92 μg/L 140 μg/L 

Lactating (n = 95) 161 μg/L (22) 25 μg/L* 29 μg/L* 81 μg/L* 109 μg/L* 

SEM = Standard Error of the Mean 

* These values are potentially unreliable in a statistical sense based on an insufficient sample size. 

Source: NAP 2000. 

The severity of iodide deficiency can be determined by the amount of iodide in the urine. 

The following table identifies the urinary iodide levels for each of the three categories of iodide 

deficiency: 

Parameter 

Classification of Iodine Deficiency 

Mild Moderate Severe 

Median Urinary Iodide Levels 99 to 50 μg/L 49 to 20 μg/L < 20 μg/L 

Source: Delange 2005, p 265. 

The NHANES III survey documents that 8.1% of males and 15.1% of females are 

moderately iodide deficient (i.e., UICs < 50 μg/L) (Hollowell 1998). The NHANES III survey 

identifies that 14.9 % ± 1.2 of the U.S. women of childbearing age are moderately iodide 

deficient and that 6.9 % ± 1.9 of pregnant U.S. women are moderately iodide deficient 

(Hollowell 1998). The number of lactating U.S. women with moderate iodide deficiency cannot 

be precisely determined due to the small sample size in the NHANES III for this category (see * 

footnote above), but appears to be about 16%. Furthermore, the NHANES III survey indicates 

that about an additional 22% (i.e., corresponding to about the 29th percentile) of U.S. pregnant 

women are mildly iodide deficient. The NHANES survey also indicates that about an additional 

26% (i.e., corresponds to about the 42nd percentile) of the U.S. lactating women are mildly 

iodide deficient. The demands of pregnancy on the thyroid cause the UIC to steady decrease 

from the first to the third trimester (Glinoer 2005). The burdens of lactation continue the trend. 

Therefore, to have a greater percentage of lactating women than pregnant women both 

moderately and mildly iodide deficient is consistent with the biology. 

The NHANES III survey also documents that the proportion of the U.S. population that 

was moderately iodide deficient was 4.5 times higher in 1988-1991 than in 1971-1974 

(Hollowell 1998). The percentage of women of childbearing age (15-44 years) who were 

moderately iodide deficient increased 3.8 from the 1971-1974 period to the 1988-1991 period 

(Hollowell 1998). Furthermore, the percentage of pregnant women who were moderately iodide 

deficient increased 6.9% from the 1971-1974 period to the 1988-1991 period (Hollowell 1998). 

Since the NHANES 2000 data do not provide iodide nutritional information for pregnant 

women, the OIG checked the current validity of the NHANES III data by evaluating the results 

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from a 2004 urinary iodide sampling of 100 consecutive healthy, pregnant women in an innercity obstetric clinic in Boston, Massachusetts (Pearce 2004). The Pearce study shows a similar 

distribution of mildly and moderately iodide-deficient pregnant women as was observed in the 

NHANES III survey (Pearce 2004). The Boston sample found 9% of the pregnant women were 

moderately deficient (i.e., < 50 μg/L UIC). The Boston sample found about 21% of the pregnant 

women (i.e., the 30th percentile) were mildly iodide deficient (i.e., UIC was greater than 50 μg/L 

but less than 100 μg/L). Finally, 49% of the Boston sample of pregnant women had UICs below 

the U.S. recommended dietary allowance (RDA) of 150 μg/L (i.e., corresponds to a daily intake 

of ~ 220 μg/day for a pregnant women). Therefore, the Boston sampling confirms that the 

percentage of iodide-deficient pregnant women has remained stable over the last decade since 

the 1988-1994 NHANES IV. 

Criticism of the NHANES III Data to Accurately Assess Iodide Deficiency 

The NAS Committee directly commented on the NHANES III survey results that 15% of 

women of childbearing age and 7% of pregnant women had UIC less than 50 μg/L (NAS 2005, 

p 46). NHANES measured UIC through a single spot (untimed) analysis. The NAS Committee 

noted, “ . . . distribution of iodide values measured in a spot urine samples is broader than values 

measured repeatedly in individual subjects (Anderson et al. 2001), this leads to overestimation of 

the number of subjects with both low and high values” (NAS 2005, p 46). In short, the NAS 

Committee’s opinion is that NHANES overestimates the percentage of U.S. women of 

childbearing age and pregnant women who are moderately iodide deficient due to the limitations 

of a single urine spot test. 

An Associate Clinical Professor of Medicine and Epidemiology of the Yale School of 

Medicine provided public comments on the same topic to California’s Draft Public Health Goal 

for Perchlorate in Drinking Water on behalf of the Lockheed Martin Corporation (Borak 2002). 

The Associate Clinical Professor indicated that the NHANES III survey “ . . . exaggerates and 

perhaps misrepresents the iodine sufficiency of the U.S. population generally and that of 

pregnant women specifically” (Borak 2002). The Associate Clinical Professor challenged the 

meaningfulness of the NHANES III survey results that indicate that 15% of women of 

childbearing age and 7% of pregnant women may be moderately iodide deficient on the 

following two perspectives: 

1. A single spot urine sample reflects very recent dietary intake rather than diet 

generally. The Associate Clinical Professor also cites the Anderson field study 

(Anderson 2001), which measured urinary iodide samples in 15 men monthly for 12 

months. The variability of urine iodide levels within a month across the individual 

samples was much greater than the variation of individual means considered across the 

population (i.e., 6.7% of individual samples were < 25 μg/L but no individual had a 

yearly average level < 25 μg/L). Therefore, in the Associate Clinical Professor’s opinion, 

the NHANES III survey results “ . . . overstates the proportion of subjects with very low 

(and very high) urinary iodide levels.” The Associate Clinical Professor suggested that if 

multiple urine samples were obtained instead of single spot samples from pregnant 

women, few (if any) would have levels of < 50 μg/L. 

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2. In a follow-up study by Hollowell (Hollowell 2002), TSH and total T4 levels were 

evaluated in the serum samples collected for the NHANES III survey. This study found 

that 0.3% had overt hypothyroidism (i.e., elevated TSH and below normal T4) and 4.3% 

had subclinical hypothyroidism (i.e., elevated TSH and normal T4). The Associate 

Clinical Professor indicated that this study found that moderate iodide deficiency does 

not predispose an individual to hypothyroidism. 

The OIG addresses these criticisms by the NAS Committee and the Associate Clinical 

Professor regarding the utility of using the NHANES III survey to estimate the frequency of 

iodide deficiency with in the U.S. population with the following comments: 

•	 The OIG’s biggest concern is that both the NAS Committee and the Associate Clinical 

Professor’s comments cite a 12-month “male” urine study. The variation in a spot urine 

sample is expected to vary because of several factors: variation in urine dilution due to 

the body’s level of hydration, diurnal iodide variation, time since last meal, and seasonal 

iodide intake variation (Demers 2003). However, the essential point is to know how the 

atypical biology of the most sensitive group (i.e., pregnant women) affects the results of 

the urinalysis. Pregnancy produces pronounced changes on the body. For the spot urine 

test, the relevant change is that renal blood flow and glomerular filtration increase, which 

leads to the increased clearance of iodide from the plasma (Glinoer 2005). This change 

in the kidneys results in a lower plasma-iodide concentration and the elevated excretion 

of iodide in the urine. Since pregnant women are both using more iodide (i.e., to provide 

for the fetus) and are losing more iodide through the kidneys, the recommended iodide 

for pregnant women is much higher (e.g., RDA of 230 μg iodide intake/day 

(WHO/UNICEF/ICCIDD RDA of 250-300 μg iodide intake/day) versus 150 μg iodide 

intake/day for an adult). Since pregnancy causes an increase in the iodide excretion rate, 

the UIC will appear higher than normal for the given level of iodide intake, thus giving a 

false reading (i.e., bias high) of the actual iodide nutrition status of the pregnant women 

(Demers 2003, p 78). Therefore, the increased excretion from the kidneys during 

pregnancy biases the UIC high, while the spot test can bias the UIC low; thus, the two 

effects probably cancel each other out. Thus, the NHANES III survey results on the rate 

of iodide deficiency in pregnant women are probably reasonable, but these results do 

represent a significant uncertainty in the science concerning this public health issue (i.e., 

what portion of the U.S. pregnant women population is moderately or mildly iodide 

deficient?). 

•	 A closely related concern is how to interrupt, for example, a UIC of 50 ug/L in pregnant 

women. A UIC of 50 ug/L in nonpregnant adults is considered to be moderately iodide 

deficient. The recommended UIC for healthy, nonpregnant adults is 100 to 200 μg/L 

(Delange 2005, p 278, table 11E.8). Therefore, the median healthy UIC value is 150 

μg/L. Thus, a UIC of 50 ug/L in nonpregnant adults is one-third of normal. However, 

the recommended healthy UIC in pregnant women is higher. Several credible sources 

have opined on the recommended UIC for pregnant women. The average recommended 

UIC for pregnant women from these opinions was 204 μg/L. The following table 

summarizes the sources and recommended UICs for pregnant women: 

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Source 

Recommended Iodide 

Intake in Pregnant Women 

(μg/day) 

Recommended Urinary 

Iodide Concentration 

(μg/L) 

WHO/UNICEF/ICCIDD* 200 200-300 

Dr. Francois Delange, MD** 225-300 150-230 

WHO Technical Consultant Group*** 225-375 150-249 

Recommend Dietary Allowances (RDA)† 220† 150†† 

Average Value => 258 204 

* Source: Delange 2005, p 278, table 11E.8. 

** Source: Delange 2004. 

*** Source: ATA 2006. 

† Source: NAP 2000. 

†† Source: Pearce 2004. 

Therefore, a UIC of 50 ug/L in pregnant women is a lower fraction of the healthly 

recommended UIC for pregnant women. A UIC of 50 ug/L in pregnant women is less 

than one-fourth the average recommended UIC level for pregnant women. A UIC of 50 

ug/L in pregnant women could be as much as one-sixth the recommend UIC level if the 

upper limit of 300 ug/L from the WHO/UNICEF/ICCIDD is used. Therefore, a UIC 50 

ug/L in pregnant women represents a greater level of iodide deficiency than the same 

corresponding UIC of 50 ug/L in nonpregnant adults. 

•	 To assess whether the NHANES III survey data overestimate the percentage of U.S. 

pregnant women with iodide deficiency, the OIG searched for an independent source of 

data that could be used to corroborate the NHANES III survey results. Iodide levels in 

human breast milk (i.e., a different excretion route) are an independent source of data that 

can be used to independently assess the iodide deficiency status of U.S. lactating women. 

The observed iodide content of human breast milk can be used to document the frequency 

of iodide deficiency in U.S. pregnant women. The WHO/UNICEF/ICCIDD uses the 

following iodide breast milk values to classify the severity of iodide deficiency in goiter 

endemic areas: 

Parameter 

Classification of Iodide Deficiency 

Mild Moderate Severe 

Iodide Levels 

In Human Breast Milk 35 to 50 μg/L 20 to 35 μg/L < 20 μg/L 

Source: Delange 1994, p 109. 

The urinary iodide results from the NHANES III survey indicate that about 42% of the 

U.S. lactating women population is iodide deficient. By comparison, three studies 

measuring the iodide content of breast milk had the following findings: 

3⁄4 Of the 23 lactating women measured for iodide in the Kirk 2005 study, the iodide 

content of the breast milk in 14 of 23 lactating women (60%) was measured to be 

iodide deficient (i.e., < 50 μg/L) (Kirk 2005). 

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3⁄4 Of the nine lactating women in the Kirk 2007 study, the iodide content of the 

breast milk in four of nine lactating women (44%) was found to be iodide 

deficient (i.e., < 50 μg/L) (Kirk 2007). 

3⁄4 Of the 57 lactating women measured for iodide in the Pearce 2007 study, the 

median iodide breast milk was reported to be 155 μg/L (range 2.7 - 1968 μg/L) 

(Pearce 2007). Since only summary statistics were provided (i.e., not individual 

results for each women), the percentage of iodide-deficient women could not be 

identified. Pearce points out that differences in analytical methods for measuring 

total iodide may explain some of the differences between the Pearce 2007 study 

and the Kirk 2005 and 2007 studies. 

Although the sampling size in these three studies is too small to adequately identify the 

distribution of iodide deficiency in the U.S. lactating population as being mild, moderate, 

or severe, the percentage of iodide-deficient lactating women in the two Kirk studies 

(60% and 44%) do independently support the conclusion from the NHANES III survey 

that about 42% of the U.S. lactating women population is iodide deficient. 

•	 Iodide surveys using the spot test (e.g., NHANES III survey, NHANES 2000, and Boston 

area study) are appropriate to identify the average UIC of a population. The inherent 

differences in urine dilution in a spot urine survey are partially compensated for by using 

a large number (~50) of subjects in each study population (Demers 2003, p 77). Due to 

these limitations, the spot test urine surveys are not well suited to accurately characterize 

the size of the high or low UICs in the population. Characterizing the high and low 

UICs in the population is critical, because the population with high and low UICs is the 

population susceptible to adverse health effects from iodide. 

•	 Additional iodide survey(s) should be designed to accurately characterize the population 

with high and low iodide intakes. Iodide intake is best determined by a 24-hour urine 

sample; however, logistics make this method impractical for epidemiological studies 

(Demers 2003, p 77). The difference in level of dilution of a spot urine sample can be 

partially compensated for using results normalized to urine creatinine (i.e., μg iodide 

excreted/gram creatinine (UI/Cr ratio)), but the diurnal and seasonal cycles of iodine and 

creatinine urinary excretion are different along with seasonal variations in iodide intake 

(i.e., higher UIC in winter) (Demers 2003). Furthermore, urinary iodide excretion can 

vary even in healthy, well-nourished individuals. The Associate Clinical Professor 

recommends taking more samples to better characterize the UIC. However, this is 

unlikely to happen because the CDC does not consider iodide nutrition to be a problem or 

priority (the NHANES 2000 survey only took 1,433 samples to measure iodide instead of 

the 21,298 samples in the NHANES III survey). Therefore, a practical substitute of the 

ideal but impractical 24-hour urine sample is the age- and sex-adjusted (UI/Cr) ratio in a 

fasting morning specimen, which comes close to the true 24-hour iodide excretion if 

nutrition is generally adequate (Demmers 2003, p 77). Since urinary iodide is diurnal and 

reaches a median early in the morning or 8-12 hours after the last meal, another practical 

substitute could be to take spot urine samples at these times (Demers 2003). 

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•	 In pregnant women with iodide deficiency, a steady decrease in UIC is seen from the first 

trimester through the third trimester, hence revealing the underlying tendency toward 

iodide deficiency associated with the pregnancy (Glinoer 2005). This steady decline in 

UIC continues through lactation. This trend is seen in the NHANES III survey data with 

the UIC of lactating women being consistently lower than the UIC of pregnant women 

for the same percentile. The point is the NHANES III data do not indicate when the spot 

urine sample was taken during the pregnancy (i.e., which trimester(s)). If the majority of 

the data points are early on in the pregnancy, the UIC might be biased high and not 

representative of the last trimester of the pregnancy. 

•	 The Associate Clinical Professor questions the association between iodide deficiency and 

hypothyroidism. The NAS Committee’s mode-of-action model assumes that pregnant 

women have to become hypothyroid before mental deficits in their children occur. 

However, the epidemiological studies of iodide deficiency in euthyroid pregnant women 

show mental deficits in their children (see hazard characterization section above for 

details). These studies indicate that the mother does not have to be hypothyroid before 

mental deficits can occur in her children. Although the mother can be euthyroid during 

iodide deficiency, the fetal thyroid is less able to adapt to the iodide deficiency, resulting 

in the possibility of permanent lifelong mental deficits. Therefore, the Associate Clinical 

Professor’s issue that the Hollowell’s study (Hollowell 2002) does not associate iodide 

deficiency with hypothyroidism is not critical to assessing the risk. By contrast, iodide 

deficiency clearly stresses the thyroid of pregnant women; this situation is only partially 

reversible during late postpartum (Glinoer 1992). 

•	 The Associate Clinical Professor points out that the spot urine samples reflect only recent 

dietary intake and not yearly averages of UIC. However, due to the speed at which the 

fetal brain develops, a 2- or 3-week period of insufficient thyroid hormones may be 

adequate to irreversibly affect the brain’s development and result in permanent, lifelong 

mental deficits in the child. This short time frame is observed in a study of the treatment 

of congenital hypothyroidism, where neonates who took longer than 2 weeks to have 

their thyroid hormone levels normalize had significantly lower cognitive, attention, and 

achievement scores than those infants who had normal thyroid function within 1 or 2 

weeks of therapy (Selva 2005). 

Assessing Iodide Exposure through the FDA Total Dietary Study 

Exposure can also be assessed by estimating the amount of dietary intake. On January 2, 

2008, FDA published a TDS measuring the dietary intake of iodide (FDA 2008). The TDS 

involved the purchase and iodide testing of 285 foods and beverages that represents the “total 

diet” of the average U.S. population. Iodide has been analyzed for in all TDS foods since 2003. 

The TDS was designed to provide a reasonable estimate of total dietary exposure to iodide from 

all foods in the diet. The contribution of iodide from each food group was determined by 

summing the estimated intakes from all TDS foods within each of the 12 food groups. The 

percentage of total intake of iodide is calculated for each food group for 14 age/sex groups. The 

percentage contribution of estimated daily intake of iodide for each food group for three age/sex 

groups is provided in the following table: 

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Total Dietary Study 

(TDS) Food Group 

Percentage Contribution (%) of Each TDS Food Group 

to the Estimated Daily Intake of Iodide for 2003-2004 

Non-Nursing Infants 

(6-11 months old) 

Children 

(6 years old) 

Women 

(25-30 years old) 

Baby Food 56 0 0 

Beverage 1 2 9 

Dairy 34 70 49 

Egg 2 2 4 

Fat/oil 0 0 0 

Fruit 2 3 3 

Grain 3 14 20 

Legume 0 0 0 

Mixture 1 5 8 

Meat, poultry, fish 0 2 3 

Sweets 0 1 2 

Vegetable 1 1 2 

Source: Murray 2008, table 6. 

The FDA TDS identifies that for 6- to 11-month-old non-nursing infants, the baby food 

group is the dominant source of iodide in the diet, contributing 56% of the total intake of iodide 

followed by the dairy food group at 34%. Likewise, the FDA TDS identifies that for 6-year-old 

children, the dairy food group is the dominant source of iodide in the diet, contributing 70% of 

the total intake of iodide. Furthermore, the FDA TDS also identifies that for 25- to 30-year-old 

women (i.e., the closest FDA age/sex group corresponding to women of childbearing age), the 

dairy food group is the dominant source of iodide in the diet, contributing 49% of the total intake 

of iodide. The FDA TDS clearly identifies that dairy and grain are the most significant sources 

of iodide in the adult diet (Murray 2008, p 7). 

The FDA TDS for iodide also determines the estimated upper and lower average iodide 

intake for each food group for 14 age/sex groups. The estimated total iodide intake for each 

age/sex group can then be compared against the estimated average requirement (EAR) and the 

RDA for each age/sex group. EARs are used to both assess the adequacy of population intakes 

and as the basis for calculating RDAs for individuals (NAP 2000). RDA is a goal for individual 

intake. RDAs are set to meet the needs of almost all (i.e., 97% to 98%) individuals in a group 

(NAP 2000). The estimated upper- and lower-bound average iodide intakes for three age/sex 

groups are provided in the following table: 

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Total Dietary Study 

(TDS) Food Group 

Range of Estimated Lower and Upper Bound 

Average Iodide Intake

 for 2003-2004 for Each Food Group (μg/person/day) 

Infants 

(6-11 months) 

Children 

(6 years old) 

Women 

(25-30 years old) 

Baby Food 82.8 - 88.3 0.0 - 0.0 0.0 - 0.0 

Beverage 0.0 - 1.8 0.1 - 11.3 0.2 - 32.1 

Dairy 50.8 - 50.8 187.9 - 188.0 83.2 - 83.2 

Egg 2.5 - 2.5 5.1 - 5.1 6.0 - 6.0 

Fat/oil 0.0 - 0.0 0.2 - 0.3 0.6 - 0.7 

Fruit 1.6 - 3.1 5.8 - 9.7 4.2 - 7.4 

Grain 3.6 - 4.1 37.1 - 39.5 32.3 - 34.8 

Legume 0.0 - 0.1 0.2 - 0.5 0.2 - 0.6 

Mixture 1.9 - 2.5 11.2 - 13.3 12.6 - 15.8 

Meat, poultry, fish 0.5 - 0.6 4.0 - 5.3 4.6 - 6.4 

Sweets 0.0 - 0.1 2.7 - 3.4 2.8 - 3.2 

Vegetable 0.6 - 1.1 1.2 - 3.9 1.4 - 5.8 

Total Iodide Intake 144 - 155 255 - 280 148 - 196 

Estimated Average Requirement (EAR) 130 65 

95 

160 (pregnancy)* 

209 (lactation)* 

Recommended Daily Allowance (RDA)* 130 90 

150 

220 (pregnancy) 

290 (lactation) 

Source: Murray 2008, table 7. 

* Source: NAP 2000. 

The range of average iodide intakes for the 6- to 11–month-old non-nursing infants 

subpopulation is above both the EAR and RDA for that subpopulation. Likewise, the range of 

average iodide intakes for the 6-year-old children subpopulation is also above EAR and RDA for 

that subpopulation. 

Similarly, the range of estimated average iodide intakes for the 25- to 30-year-old women 

subpopulation is above the EAR for nonpregnant women of this subpopulation. However, the 

FDA TDS does not estimate intakes for subgroups with specific nutritional needs (e.g., pregnant 

or lactating women). However, the iodide intake of pregnant and lactating women is the critical 

information needed to assess the risk from this public health issue. Pregnant and lactating 

women have increased caloric needs, which would likely result in “somewhat higher” iodide 

intake values (Murray 2008, p 8). From a population standpoint, and considering the added food 

intake of pregnant and lactating women, the range of estimated average iodide intakes for the 25- 

to 30-year-old women subpopulation of 148–196 μg/person/day generally meets the EARs of 95, 

160, and 209 μg/person/day for women, pregnant women, and lactating women of this age 

group. However, even when considering the added food intake of pregnant and lactating women 

(e.g., estimated at 20% more), the increased estimated average iodide intakes for pregnant and 

lactating women has difficulty meeting the RDAs of 220 and 290 μg/person/day for pregnant 

and lactating women. In other words, if the average intake of iodide for a population just meets 

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the RDA, this means that half of the pregnant and lactating women (i.e., the individuals below 

the average intake of iodide) are below the RDA for pregnant and lactating women. This finding 

from the FDA TDS for iodide is fully consistent with the observation that 49% of the Boston 

sample of pregnant women in the Pearce study had UICs below the U.S. RDA of 150 μg/L 

pregnant women (i.e., corresponds to a daily intake of ~ 220 μg/day for a pregnant woman) 

(Pearce 2004). Furthermore, this finding from the TDS for iodide is in agreement with the 

NHANES III results indicating the 50th percentile of pregnant women (i.e., UIC of 140 μg/L) is 

below the U.S. RDA of 150 μg/L for pregnant women. Therefore, if the iodide exposure 

assessment is done by measuring iodide excretion or by measuring iodide intake by food 

consumption, the iodide exposure assessment comes to the same conclusion that about half (i.e., 

50%) of the pregnant women are below the RDA for iodide. 

The FDA TDS does not provide the required information needed to evaluate and quantify 

the risk in the most sensitive group, pregnant women. The perchlorate and iodide intakes in 

pregnant women are needed assess the risk to pregnant women. The perchlorate intake is 

essential to quantify the total amount of NIS inhibition occurring in pregnant women. 

Furthermore, iodide intake is also essential in quantifying the amount of TIU occurring in 

pregnant women. However, the design of the FDA TDS did not identify pregnant women as one 

of the 14 age/sex population groups in the study (Murray 2008, p 8). 

The perchlorate and iodide intake in pregnant women is needed to characterize the 

perchlorate and iodide exposure occurring in nursing infants. A nursing mother will pass her 

perchlorate exposure level (as well as her thiocyanate and nitrate exposoure level) and iodide 

nutrition level onto her nursing infant. In a cumulative risk assessment, the exposure level to all 

four NIS stressors in pregnant women must been known and is essential to assessing the risk to 

nursing infants. However, the FDS TDS does not provide this sought after exposure information 

in pregnant women. The perchlorate and iodide intakes for pregnant women were not 

incoporated into the design of the FDS TDS (Murray 2008). 

Another critical limitation of the FDA TDS study is that the distribution of iodide intake 

is not determined in pregnant women. The FDA TDS only determined the statistical range of the 

average iodide intake. This type of information is useful to evaluate whether the median iodide 

dietary intake in a population is reasonable. However, adverse health effects from iodide intake 

in pregnant women occur at the extremes (i.e., the upper and lower 10%). For this public health 

issue, subtle mental deficits in children occur in either pregnant women who are mildly or 

moderately iodide deficient. The percentage of pregnant women with low iodide intake (i.e., 

poor iodide nutrition) is a critical piece of information for the cumulative risk assessment of this 

public health issue. Unfortunately, the FDA TDS was neither designed for nor provides 

nutritional information on the proportion of the U.S. pregnant women subpopulation that is either 

mildly or moderately iodide deficient. 

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Iodide Exposure Assessment of the Fetus and Nursing Infant is Directly Related 

to the Mother’s Iodide Status 

Since the mother is the sole provider of both thyroid hormones and iodide to the 

developing fetus during pregnancy, the mother’s iodide status can directly affect the developing 

fetus. The fetal thyroid becomes operational only after midgestation (Glinoer 2005, p 1095). 

During the first and second trimester, the developing fetus is almost exclusively dependent on 

the mother to provide an adequate supply of thyroid hormones for proper brain development 

(Glinoer 2005). However, by the third trimester, the supply of thyroid hormones is of 

essentially fetal origin, but the fetus is still dependent on the mother for an adequate supply of 

iodide for proper brain development (Glinoer 2005). 

During lactation, the mother provides the nursing infant with iodide. The mother’s iodide 

status can directly affect the developing infant. The regulation of iodide into breast milk is only 

partially known (Laurberg 2002). However, study results observed in Danish mothers indicate 

that iodide content of breast milk seems to vary in parallel with the iodide intake of the mother 

(Nohr 1994; Laurberg 2002, figure 1). The results of the iodide study of Danish mothers and 

infants are summarized below: 

Iodide Ratio Evaluated 

Ratio 

(median) 

Percentiles 

(25% - 75%) 

Number 

Tested 

Ratio of iodide concentration in breast milk to the 

mother’s urinary iodide concentration 0.96 0.50-1.96 n = 142 

Ratio of infant’s urinary iodide concentration to 

mother’s iodide breast milk concentration 1.00 0.60-1.64 n = 137 

Ratio of infant’s urinary iodide concentration to 

the mother’s urinary iodide concentration 1.00 0.65-1.75 n = 141 

In other words, this study indicates that, on average in a population, the iodide status of 

the mother is directly reflected in the iodide concentration of her breast milk. As the breast milk 

is subsequently consumed by the infant, on average in a population, the infant’s iodide status is 

directly related to the mother’s iodide concentration in her breast milk. As such, on average in a 

population, the mother’s iodide status directly corresponds to the iodide status of the nursing 

infant. Therefore, during lactation, the iodide nutritional status of the lactating mother is a good 

measure of the iodide nutritional status of the nursing child (Laurberg 2002). For example, if the 

lactating mother is moderately iodide deficient, then it is reasonable to expect the nursing infant 

to be also moderately iodide deficient. 

The Size of the U.S. Sensitive Population Potentially Affected by the Lack of 

Iodide 

The final task in the iodide exposure assessment is to determine the size of the U.S. 

sensitive population potentially affected by the lack of iodide. Although about half of pregnant 

women are iodide sufficient (i.e., RDA for pregnancy of 150 μg/L (Pearce 2004)), a significant 

portion of the sensitive groups (i.e., pregnant women, fetuses, neonates born with elevated TSH 

levels, and nursing infants) have either mild or moderate iodide deficiency. The following table 

provides an estimate of the size of each of the sensitive groups: 

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Severity 

of Iodide 

Deficiency Sensitive Population 

Percentage of 

4 Million Annual 

U.S. Births 

Estimated U.S. 

Population Potentially 

Affected Per Year 

Pregnant Women/Fetuses 6.9% 276,000 

Moderately 

Elevated TSH Neonates (Occurrence 

rate of 17.0% to 36.9% rate above 

iodide sufficient rate up to 3%) 

1.2% to 2.5% 

(i.e., 0.069 x 0.17; 

and 0.069 x 0.369) 48,000 to 100,000 

Nursing Infants 

3.7% 

(i.e., 0.069 x 0.53 

nursing frequency) 148,000 

Pregnant Women/Fetuses 22% 880,000 

Mildly 

Elevated TSH Neonates 

(Occurrence rate of 0% to 16.9% rate 

above iodide sufficient rate up to 3%) 

0% to 3.7% 

(i.e., 0.22 x 0.0; 

and 0.22 x 0.169) 0 to 148,000 

Nursing Infants 

11.7% 

(i.e., 0.22 x 0.53 

nursing frequency) 468,000 

The NHANES III survey identifies that about 6.9% of the U.S. pregnant women are 

moderately iodide deficient. Since the United States has about 4 million births per year (Martin 

2003), up to approximately 276,000 children are born every year to moderately iodide-deficient 

mothers in the United States (4,000,000 births x 0.069). Therefore, up to 276,000 children are 

potentially affected every year by the more severe adverse effects associated with low maternal 

TIU during pregnancy (i.e., maternal UIC less than 50 ug/L). 

In addition, the NHANES III survey can be used to identify the percenation of U.S. 

pregnant women who are mildly iodide deficient. The NHANES III survey identifies 

approximately the 29th percentile of U.S. pregnant woman population as having a UIC less than 

100 μg/L and therefore, as being iodide deficient. The percentage of U.S. pregnant women who 

are mildly iodide deficient can be estimated by taking the total number of iodide-deficient 

pregnant women (i.e., 29%) and subtracting the number of moderately iodide deficient pregnant 

women (i.e., 6.9%). Therefore, approximately 22% (i.e., 29% - 6.9%) of the U.S. pregnant 

woman population is estimated to be mildly iodide deficient. Since the United States has about 4 

million births per year (Martin 2003), up to approximately 880,000 children are born every year 

to moderately iodide-deficient mothers in the United States (i.e., 4,000,000 births x 0.22). 

Therefore, up to 880,000 children are potentially affected every year by the minimal adverse 

effects associated with low maternal TIU during pregnancy (i.e., maternal UIC between 50 and 

100 ug/L). 

The neonatal TSH level at birth is the principal indicator that identifies fetal thyroid stress 

and focuses on the potential for neonatal brain damage (Delange 1998). Due to the importance 

of this indicator, the iodide exposure assessment estimates the number of elevated TSH neonates 

above the baseline rate observed in iodide-sufficient populations to be 0 to 148,000 and 48,000 

to 100,000 neonates per year in mildly and moderately iodide-deficient populations, respectively. 

This is the portion of the population that may have partially impaired thyroid function, which 

makes it particularly susceptible to iodide deficiency. 

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The nursing infant’s brain is still developing and still vulnerable to an insufficient uptake 

of iodide by the thyroid. The nursing infant’s iodide nutritional status is directly related (i.e., a 

ratio of 1.00) to the iodide nutritional status of the mother (Nohr 1994; Laurberg 2002, figure 1). 

From a population standpoint (i.e., not an individual standpoint), a moderately iodide-deficient 

nursing mother is likely to have a moderately iodide-deficient nursing infant. Therefore, the 

number and level of iodide deficiency in nursing infants can be estimated from the number and 

level of iodide-deficient mothers. Furthermore, the fact that not all mothers breastfeed has to be 

factored into the estimate. At least 53.6% ± 1.7 of U.S. infants are breastfed at least once, while 

22.4% ± 1.2 of U.S. infants are breastfed at 6 months (Li 2002). Therefore, the iodide exposure 

assessment estimates the number of U.S. nursing infants with mildly and moderately iodide 

deficiency to be up to 468,000 and 148,000, respectively. 

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9. TIU Cumulative Risk Assessment 

Unlike a conventional single chemical exposure assessment, a cumulative risk 

assessment accounts for all the known stressors associated with a public health issue. 

Cumulative risk assessment expands our understanding of the public health impacts of 

environmental exposures (Fox 2004) and provides a clearer, more complete picture of a public 

health issue for making risk management decisions (EPA 2003, appendix A). Cumulative risk 

assessment will reduce risks to the extent that it can be integrated into prevention strategies to 

track and protect public health (Fox 2004). Therefore, this cumulative risk assessment must 

account for the following known stressors affecting this public health issue: 

1.	 The amount of NIS inhibition from thiocyanate. 

2.	 The amount of NIS inhibition from nitrate. 

3.	 The amount of NIS inhibition from perchlorate. 

4.	 The lack of iodide in the diet. 

5.	 The heterogeneous thyroid performance within the human population. 

6.	 The interference of the other major steps in the use of thyroid hormones (e.g., production, 

transport, and peripheral tissue metabolism). 

The OIG’s approach to conducting a cumulative risk assessment is to apply the NAS 

Toxicity Testing Committee’s vision for toxicity testing to this public health issue. The NAS 

Toxicity Testing Committee’s vision of toxicity testing is to develop a quantitative, mechanistic, 

dose-response model of the cellular pathway that is perturbed by the stressor(s) (NAS 2007). 

Subsequent pharmacokinetic modeling would identify a safe human exposure level that prevents 

the environmental chemical from reaching a toxic tissue concentration. The NAS Toxicity 

Testing Committee’s vision takes advantage of advances in science (e.g., proteomics and 

genomics) in which the increased understanding of the biological mechanisms allows in vitro 

toxicity testing to be applied to environmental risk assessments. As the complexity of the risk 

assessment increases (i.e., more factors evaluated), animal testing is neither practical nor 

sensitive enough to observe and define the relationship between an increasing number of 

stressors. For example, four stressors each administered at three different doses (i.e., high, 

medium, and low) would require 81 separate animal studies to evaluate all the possible 

combinations (i.e., 34

). To conduct 81 Argus-equivalent perchlorate rat studies is impractical. 

Furthermore, no scientific techniques are available to measure subtle cognitive deficits in rat 

offspring. These limitations in conventional animal testing require the implementation of NAS 

Toxicity Testing Committee’s vision of toxicity testing in order to characterize the risk from 

exposure to the four NIS stressors. 

A quantitative, mechanistic, dose-response model of the NIS cellular pathway is available 

in the published literature. The Tonacchera Model is a multifactorial mathematical equation that 

characterizes the biological performance of the NIS to uptake iodide to the simultaneous 

exposure to all four NIS stressors (Tonacchera 2004). The Tonacchera Model defines the 

relationship between the four NIS stressors (1-4 listed above) and the TIU by the NIS. 

Therefore, the use of the Tonachera Model results in a single variable, the TIU, that measures the 

resulting cumulative effect (i.e., integrated effect) of the simultaneous exposure to all four NIS 

stressors. Since a low TIU result triggers the subsequent adverse effects, knowing the relative 

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combinations of the four NIS stressors that result in a low TIU is critical to addressing this public 

health issue. In order to define the combination of the four NIS stressors that result in an 

unacceptably low TIU requires the development and implementation of a cumulative risk 

assessment. 

The OIG is using of the Tonacchera Model to conduct a cumulative risk assessment 

that incorporates the four NIS stressors. This is in contrast to the outdated approach of a single 

chemical risk assessment (EPA 1992; NAS 1994; EPA 1997b; EPA 2000; Callahan 2007). 

Nevertheless, with any environmental model, any results need to be corroborated with other 

independent sources of information (e.g., predicted level of stressor exposure is observed to 

result in adverse effects in humans) (EPA 2003a). 

In order to conduct a cumulative risk assessment, the exposure to each of the stressors 

must be characterized. The human exposure to perchlorate and lack of iodide is relatively well 

characterized. By contrast, the human exposure to thiocyanate and nitrate is less well 

characterized. Therefore, this cumulative risk assessment uses only the typical thiocyanate and 

nitrate exposure levels in the U.S. population to demonstrate the application of cumulative risk 

assessment to this public health issue. Ideally, the exposure distribution of thiocyanate and 

nitrate in the U.S. population would be a useful piece of information. The 90th percentile 

thiocyanate exposure of nonsmokers in the U.S. population would be useful in the subsequent 

modeling. Likewise, the 90th percentile of nitrate exposure in the U.S. population would also be 

useful in the subsequent modeling. 

9.1 Corroboration of Tonacchera Model with Effects Observed in Humans 

The Tonacchera Model must be corroborated with effects observed in humans before 

being used for risk characterization and before being used to define an RfD based on a %TIU 

level. Section 3.1.3 of EPA’s Draft Guidance on the Development, Evaluation, and 

Application of Regulatory Environmental Models (November 2003) establishes the need to 

corroborate all environmental models before risk assessors use the models as the basis of rule 

making or regulation (EPA 2003a). The Tonacchera Model represents an environmental model 

that calculates the TIU by the thyroid based on the environmental exposure to all four NIS 

stressors. As such, the Tonacchera Model results must be corroborated with effects observed 

in humans. This corroboration is performed in this section of the OIG Analysis. 

“Robustness” is an aspect of model corroboration. Section 3.1.3.2 of EPA’s Draft 

Guidance on the Development, Evaluation, and Application of Regulatory Environmental 

Models defines robustness as the capacity of a model to perform equally well across the full 

range of environmental conditions (EPA 2003a). A model cannot be corroborated against the 

data or similar data used to generate or calibrate the model. An independent measure of the 

model’s performance is that the model agrees with results from other sources of data. Since 

the Tonacchera Model is derived from in vivo data, all human results represent potential 

corroboration from a different data source. The OIG Analysis corroborates the Tonacchera 

Model in Sections 9.1.1 through 9.1.6. The corroboration of the Tonacchera Model is robust 

because of the multiple points of agreement and the ability to explain the basis of the observed 

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effect across a variety of human data sources and types. The major points of corroboration are 

(see the individual sections in 9.1 for a more detailed explanation): 

•	 The calculated %TIU levels for adverse thyroid effects from chronic excess NIS 

inhibitor exposure in both men and women is consistent with the NAS 

Committee’s statement that a 75% reduction in TIU would be needed to induce 

adverse effects in adults (which is not the sensitive group) (see Section 9.1.1). 

•	 The Tonacherra Model calculates lower %TIU levels for the more severe 

thyroid condition, hypothyroidism, than for the less-severe thyroid condition 

hypothyroxinemia (see Sections 9.1.2 and 9.1.3). 

•	 The calculated %TIU levels for adverse thyroid effects from chronic excess NIS 

inhibitor exposure show that women are more prone than men to adverse 

thyroid effects induced by a low TIU, which is consistent with clinical 

observations (see Sections 9.1.2 and 9.1.3). 

•	 The Tonacchera Models calcluates a decrease in %TIU that agrees with the 

measured radioactive iodide uptake (RAIU) levels in both the Greer Perchlorate 

Exposure Study and the Braverman Perchlorate Occupational Exposure Study 

(see Sections 9.1.4 and 9.1.5). 

•	 The findings from the Tonacchera Model on the role and contribution of each of 

the NIS stressors to this public health issue are consistent with the role and 

contribution of iodide and NIS inhibition on the etiology of endemic cretinism, 

which occurs through the same mechanism of toxicity (see Section 9.1.6). 

•	 The Tonacchera Models provides a quantified, scientific explanation as to why 

there are no observed health effects from the exposure to 119 ug of perchlorate 

per day in the Chilean epidemiological studies (see Section 6). 

A major uncertainty in the science concerning this public health issue is how much of a 

reduction in the TIU causes an adverse effect in a pregnant woman, a fetus, or a nursing 

neonate. In other words, the TIU level associated with adverse effects has not been specifically 

identified. However, the NAS Committee estimated that a 75% reduction in TIU would be 

needed to induce adverse effects. Specifically, the NAS Committee states, “To cause declines 

in thyroid hormone production that would have adverse health effects, iodide uptake would 

most likely have to be reduced by at least 75% for months or longer” (NAS 2005, p 8). 

Scientific criticism of the NAS perchlorate assessment states that this NAS statement was not 

supported by any data, analysis, or references (Ginsberg 2005). Furthermore, a member of the 

NAS Committee stated to the Massachusetts Department of Environmental Protection’s 

Advisory Committee on Health Effects that the 75% value was not derived by any quantitative 

analysis but was based on a clinical observation that a loss of a large fraction of the thyroid can 

be tolerated in adults (MassDEP 2006). The essential point is the 75% reduction in TIU was 

not determined experimentally from exposure to any of the four stressors and was not 

determined for the sensitive group: pregnant women and their fetuses (i.e., NAS 

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characterization of the tolerance of nonpregnant adults is potentially not protective of the 

sensitive group). To emphasize the limitations of this NAS statement, the concern for the 

sensitive group can be restated as a question: Can a pregnant woman with three-quarters of 

her thyroid removed still have enough thyroid hormone production during the added stress 

occurring during gestation and lactation to have a healthy child without any mental deficits? 

The TIU level associated with adverse effects must be identified or estimated. However, 

determing TIU levels in humans is impractial because of the need to conduct radioactive 123I 

uptake measurements. By contrast, the Tonacchera Model is able to calculate a TIU level for a 

given set of exposures to all four NIS stressors in both the human population in general and in 

the sensitive groups of concern (i.e., pregnant women, fetuses, and nursing neonates). This 

allows the TIU levels associated with adverse effects to be identified and compared to normal 

TIU level observed in a healthy human adult. However, the accuracy of the Tonacchera Model 

to estimate TIU levels must be corroborated with observed human data and information. The 

corroboration of the Tonacchera Model is performed in remainder of Section 9.1. 

9.1.1 NAS Hypothyroidism Statement 

The Tonacchera Model indicates that the TIU is directly proportional to the concentration 

of free iodide in the serum when the total goitrogen load is held constant (see below). 

The Tonacchera Model states that 

 TIU || [I-] / (1.22 + (SPEC)) 

where the symbol || means “proportional to.” 

If the SPEC is held constant (i.e., the level of NIS inhibitors remains the same), then 

 TIU || [I-

] 

Thus, 

 TIU(Hypothyroidism) || [I-

](Hypothyroidism) 

The [I-] in Tonacchera Model is the internal concentration of free iodide in the blood 

serum that is able to directly interact with the NIS. Unfortunately, free iodide concentrations are 

rarely reported. Healthy levels of inorganic iodide concentrations in serum are very minute and 

are about 1 pg/dL (Demers, 2003, p 77). Because of the difficulty in measuring PII, the 

measurement of PII is limited to research studies in pregnancy. Likewise, determining the 

iodide intake from the iodide content of food is extremely difficult for methodological reasons 

(Delange 2005, p 267). Therefore, the median urinary concentration is the most practical 

measurement of iodide intake in a population (Dunn 1998). Iodide balance studies have shown 

that adults are in balance with their iodide environment (Delange 2005, p 267). About 90% of 

ingested iodide is excreted in the urine (Dunn 1998), while usually a negligible amount (i.e., 5 

μg/day) is excreted in fecal matter. Therefore, in general terms, iodide intake is proportional to 

urinary elimination. Thus, the UIC is used as a surrogate measure for the iodide concentration in 

the serum. 

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The NAS Committee states, “Hypothyroidism occurs only if daily iodide intake is below 

about 10 to 20 μg (about one-fifth to one-tenth of the average intake in the United States) [an 

intake of only 10 to20 μg of iodide equates to severe iodide deficiency]” (NAS 2005, p 6). The 

recommended iodide intake is 150 μg/day for an adult (Delange 2005, p 278, table 11E.8). 

Therefore, the estimated TIU at which hypothyroidism occurs can be estimated by the ratio of 

iodide intake associated with hypothyroidism (i.e., range of 10 to 20 μg/day) to a healthy iodide 

intake of 150 μg/day for an adult. Therefore, the TIU(Hypothyroidism) = ( range of 10 to 20 μg/day ÷ 

150 μg/day) x 100%) = range of 6.7% to 13.3%. However, the NAS Committee statements that 

10 – 20 ug of iodide per day is “about one-fifth to one-tenth of the average intake in the United 

States.” This description of a daily iodide intake of 1/5th to 1/10th corresponds to a 

TIU(Hypothyroidism) = 10% to 20%. 

The recommended UIC for a healthy adult is 100 to 200 μg/L (Delange 2005, p 278, 

table 11E.8). Therefore, the median healthy UIC value is 150 μg/L. Severe iodide deficiency is 

characterized by a UIC of < 20 μg/L (Delange 2005, p 265, table 11E.3). Severe iodide 

deficiency can generate symptoms of hypothyroidism (i.e., low T4; high TSH) (Delange 2005, 

p 272, table 11E.6). Therefore, the estimated TIU at which hypothyroidism occurs can be 

estimated by the ratio of UIC of severe iodide deficiency to median healthy UIC value. 

Therefore, the TIU(Hypothyroidism) = (20 μg/L ÷ 150 μg/L) x 100%) = 13.3%. 

In summary, from the estimates made above from the NAS Committee’s hypothyroidism 

statement, the TIU(Hypothyroidism) is expected to occur in range from 6.7% to 20% with the low 

teens being most probable (i.e., 13.3%). This is consistent with the NAS Committee statement: 

“To cause declines in thyroid hormone production that would have adverse health effects, iodide 

uptake would most likely have to be reduced by at least 75% for months or longer” (NAS 2005, 

p 8). In other words, the TIU(Hypothyroidism) is expected to occur at 25% or less. 

9.1.2 Hypothyroxinemia in Men Exposed to Excess Thiocyanate 

The TIU level at which overt hypothyroidism (i.e., elevated TSH and below-normal T4) 

or subclinical hypothyroidism (i.e., elevated TSH and normal T4) is not known by experimental 

data. However, hypothyroxinemia is a less-severe thyroid condition and is a common condition 

in pregnant women, characterized by low maternal fT4 levels with normal TSH levels (Kooistra 

2006). Maternal hypothyroxinemia is documented to be associated with mental deficits (e.g., 

ADHD) in children (Vermiglio 2004). Iodide deficiency induces thyroid changes, characterized 

by low serum T4, normal or slightly elevated T3, and a normal TSH level (i.e., as a consequence 

of the normal or elevated T3) (Obregon 2005). Therefore, iodide deficiency induces thyroid 

changes consistent with hypothyroxinemia. Since both the lack of iodide and NIS inhibitors act 

through the same mechanism of action, an excess NIS inhibitor exposure will also induce thyroid 

changes consistent with hypothyroxinemia, observed during iodide deficiency (i.e., a low TIU). 

Severe hypothyroxinemia is observed in thiocyanate-exposed electroplating workers in 

the Banerjee adult male thiocyanate study (Banerjee 1997). The thiocyanate-exposed workers 

were measured with below normal T4, just slightly below normal T3 levels, and statistically 

elevated TSH levels, but the TSH levels are still in the normal range. The exposed workers were 

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measured to have a serum thiocyanate exposure of 316 ± 15.0 μmol/L. The observations of the 

Banerjee study are summarized below: 

Banerjee Study Group 

Thiocyanate 

(μmol/L) 

T4 

(μg/dL) 

T3 

(μg/dL) 

TSH 

(μU/ml) 

35 Nonexposed Workers 

(all nonsmokers) 90.8 ± 9.02 6.09 ± 0.601 111.0 ± 9.3 1.20 ± 0.301 

35 Exposed Workers 

(all nonsmokers) 316 ± 15.0* 3.81 ± 0.318† 57.2 ± 8.1† 2.91 ± 0.20† 

Normal Ranges Cited in the 

Manufacturers Test Kits 

_ 

5.5 to 13.5 60 to 200 0.2 to 4.0 

* p < 0.01 

† p < 0.05 

Source: Banerjee 1997, table 1. 

The Tonacchera Model can be used to calculate the TIU level that corresponds to the 

hypothyroxinemia observed in the exposed workers in the Banerjee thiocyanate adult male study. 

The TIU calculations are as follows: 

The Tonacchera Model states: 

 TIU || [I-] / (1.22 + (SPEC)) 

where the symbol || means “proportional to”. 

If the [I-] is held constant, a normal [I-] level is assigned the variable “x.” (Note: the 

variable x corresponds to the normal [I-] level in the U.S. population of 145 μg/L), then 

the TIU for normal U.S. exposure (i.e., to be used as the normal TIU reference point) to 

the four NIS variables is given by the following: 

TIU(Normal) || x_____ _ 

(1.22 + SPEC(Normal)) 

Since SPEC(normal) was previously calculated in this paper to be 1.501 μmol/L from the 

median exposures to thiocyanate (SCN-

), nitrate, and perchlorate in the U.S. population, 

TIU(normal) is: 

TIU(Normal) || x___ 

(1.22 + 1.50

_ 

1) 

TIU(Normal) || x_ _ 

(2.721) 

TIU(Normal) || 0.3675x 

In the Banerjee thiocyanate adult male study, the iodide nutritional level was not 

determined (which is typical in the epidemiological studies in that they measure only a 

subset of the four NIS stressors). However, the iodide nutritional level of the 

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thiocyanate-exposed workers is believed to be sufficient due to the year and location of 

the study (Gibbs 2006). However, a different Banerjee study did measure the iodide 

nutritional level in 70 test subjects in India in the same year (Banerjee 1997a). A random 

sampling of UIC in 50 to 100 people can be used to define the iodide nutritional status of 

a population (Delange 2005, p 267). In the Banerjee thiocyanate women study, the 

average UIC of 70 subjects was 119 μg/L (i.e., avg. 115 μg/L and 123 μg/L). Therefore, 

a UIC of 119 μg/L (i.e., 0.82x) is a reasonable value to use for the TIU(Hypothyroxinemia) 

calculation in the exposed workers. The TIU(Hypothyroxinemia) calculation will also be been 

done using the UIC found in the U.S. population of 145 μg/L in order to define an upper 

limit for the TIU(Hypothyroxinemia) range. Thus, assuming a UIC of 119 μg/L, then the 

TIU(Hypothyroidism) observed in the workers is given by: 

TIU(Hypothyroxinemia) || 0.82 x_____ __

 (1.22 + SPEC(SCN -

Exposed Workers)) 

Since SPEC(SCN -

 exposed workers) is given by: 

SPEC(SCN -

exposed workers) = (ClO4

- Inhibition) + (NO3- Inhibition) + (free SCN- Inhibition) 

SPEC(SCN -

exposed workers) = [ClO4

-

] + [NO3

-

] /240 + ([total serum SCN-] x 0.528) /15 

The amount of perchlorate and nitrate exposure is not measured in the Banerjee 

thiocyanate study, but the default values observed in the U.S. population for perchlorate 

and nitrate are used for the calculation: 

SPEC(SCN -

 exposed workers) = 0.0013 μmol/L + 0.167 μmol/L + (316 μmol/L SCN- x 0.528) /15 

SPEC(SCN -

 exposed workers) = 0.0013 μmol/L + 0.167 μmol/L + 11.12 μmol/L 

- SPEC(SCN exposed workers) = 11.29 μmol/L 

Inserting 11.29 μmol/L for SPEC(SCN-

 exposed workers) 

TIU(Hypothyroxinemia) || 0.82x_____ 

(1.22 + 11.29) 

TIU(Hypothyroxinemia) || 0.066x 

The %TIU(Hypothyroxinemia) in the thiocyanate-exposed adult male workers is given by the 

following equation:

- %TIU(Hypothyroxinemia) = (TIU(SCN exposed workers) ÷ TIU(Normal)) x 100% 

= (0.066x ÷ 0.3675x) x 100% 

= 18.0 % 

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Assuming the UIC of the exposed workers was 119 μg/L, the amount of NIS inhibition 

from the thiocyanate in the exposed workers resulted in a calculated TIU(Hypothyroxinemia) of 18.0% 

as compared to the normal TIU observed in the U.S. population. Assuming the UIC of the 

exposed workers was the same as the U.S. population (i.e., 145 μg/L), the amount of NIS 

inhibition from the thiocyanate in the exposed workers results in a calculated TIU(Hypothyroxinemia) 

(calculation not shown, but identical to the above expect “0.82x” is replaced with just “x”) of 

21.8% as compared to the normal TIU observed in the U.S. population. 

In summary, as calculated from measurements from the Banerjee adult male thiocyanate 

study, a %TIU(Hypothyroxinemia) in the range of 18.0% to 21.8% is shown to induce a T3 and T4 

thyroid hormone deficiency in adult males consistent with severe hypothyroxinemia. Since 

hypothyroxinemia is a less-extreme thyroid condition than hypothyroidism, %TIU(Hypothyroidism) 

should be less than the %TIU(Hypothyroxinemia). From the estimates made above from the NAS 

Committee’s hypothyroidism statement, the %TIU(Hypothyroidism) is estimated to occur in a range 

from 6.7% to 20%, with the low teens typical (i.e., 13.3%). The %TIU(Hypothyroxinemia) in males is 

in the range of 18.0% to 21.8%, which is above the TIU(Hypothyroidism) (i.e., low teens). The 

calculation of %TIU(Hypothyroxinemia) for severe hypothyroxinemia in men was performed to 

corroborate that the results from Tonacchera Model is consistent with information from other 

sources (e.g., the clinical observations of the NAS experts). 

9.1.3 Hypothyroxinemia in Women Exposed to Excess Thiocyanate 

 Hypothyroxinemia (i.e., below normal T4 and normal T3 and TSH levels) is observed in 

thiocyanate-exposed females in the Banerjee adult female thiocyanate study (Banerjee 1997a). 

In Calcutta, India, 30-50 mg/L of thiocyanate is added to preserve milk by activating the 

lactoperoxidase-thiocyanate-hydrogen peroxide system (LP system) found in milk in order to 

retard the growth of bacteria. The thiocyanate-exposed females are measured to have below 

normal T4, and both normal T3 levels and statistically elevated TSH levels, but the TSH levels 

are still in the normal range. The exposed females were measured to have a serum thiocyanate 

exposure of 230 ± 10.0 μmol/L. The observations of the Banerjee study are summarized below: 

Study Group 

Thiocyanate 

(μmol/L) 

T4 

(nmol/L) 

T3 

(nmol/L) 

TSH 

(μU/ml) 

35 Nonexposed Females 

(all nonsmokers) 90.8 ± 9.0 125.4 ± 11.5 1.71 ± 0.16 1.09 ± 0.28 

35 Exposed Females 

(drank SCN­

 preserved milk) 230.0 ± 10.0* 87.8 ± 6.6* 2.39 ± 0.32 2.49 ± 0.20* 

Normal Ranges Cited in the 

Manufacturers Test Kits 110 to 279 0.93 to 3.12 0.2 to 4.0 

.* p < 0.01 

Source: Banerjee 1997a, table 1. 

The Tonacchera Model can be used to calculate the TIU level that corresponds to the 

hypothyroxinemia observed in the exposed women in the Banerjee thiocyanate adult female 

study. The TIU calculations are as follows: 

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The Tonacchera Model states: 

 TIU || [I-

] / (1.22 + (SPEC)) 

where the symbol || means “proportional to” 

If the [I-] is held constant, a normal [I-] level is assigned the variable “x,” then the TIU for 

normal U.S. exposure (i.e., to be used as the normal TIU reference point) to the four NIS 

variables is given by the following: 

TIU(U.S. normal) || x_____ _

 (1.22 + SPEC(U.S. normal)) 

Since SPEC(normal) was previously calculated in this paper to be 1.501 from median 

exposures to thiocyanate, nitrate, and perchlorate in the U.S. population, TIU(normal) is: 

TIU(U.S. normal) || x__ _ _

 (1.22 + 1.501 μmol/L) 

TIU(U.S..normal) || x_ _

 (2.721) 

TIU(U.S. normal) || 0.3675x 

In the Banerjee thiocyanate adult female study, the iodide nutritional level was measured. 

The average UIC in the expose females was determined to be 115 μg/L (SE 8.5). Since 

the iodide nutritional level in the U.S. population is 145 μg/L, the [I-] level in the exposed 

workers is assigned a value of 0.793x (i.e., 115 μg/L ÷ 145 μg/L). Thus, then the 

TIU(Hypothyroidism) observed in the workers is given by: 

TIU(Hypothyroxinemia) || 0.793x_____ __

 (1.22 + SPEC(SCN -

Exposed Females)) 

Since SPEC(SCN -

 exposed females) is given by: 

SPEC(SCN -

 exposed females) = (ClO4

-

 Inhibition) + (NO3

- Inhibition) + (free SCN-

 Inhibition) 

SPEC(SCN -

 exposed females) = [ClO4

-

] + [NO3

-

] /240 + ([total serum SCN-] x 0.528) /15 

The amount of perchlorate and nitrate exposure is not measured in the Banerjee 

thiocyanate study, but the default values observed in the U.S. population for perchlorate 

and nitrate are used for the calculation: 

SPEC(SCN -

 exposed females) = 0.0013 μmol/L + 0.167 μmol/L + (230 μmol/L SCN- x 0.528) /15 

SPEC(SCN -

 exposed females) = 0.0013 μmol/L + 0.167 μmol/L + 8.096 μmol/L 

137
 
 

 

 

 

 

 

 

 

10-P-0101 

- SPEC(SCN exposed females) = 8.26 μmol/L 

Inserting 8.26 μmol/L for SPEC(SCNExposed Females) 

TIU(Hypothyroxinemia) || 0.793x_____ 

(1.22 + 8.26) 

TIU(Hypothyroxinemia) || 0.0836x 

The %TIU in the thiocyanate exposed females is given by the following equation: 

- %TIU(Hypothyroxinemia) = TIU(SCN exposed females) ÷ TIU(U.S. normal) x 100% 

%TIU(Hypothyroxinemia) = (0.0836x ÷ 0.3675x) x 100% 

%TIU(Hypothyroxinemia) = 22.7% 

The amount of NIS inhibition from the thiocyanate in the exposed females resulted in a 

calculated %TIU(Hypothyroxinemia) of 22.7% as compared to the normal TIU observed in the U.S. 

population. The Banerjee thiocyanate adult female study, a %TIU(Hypothyroxinemia) of 22.7% is 

observed to induce hypothyroxinemia in females. Since hypothyroxinemia is less extreme 

thyroid condition than hypothyroidism, %TIU(Hypothyroidism) should be less than the 

%TIU(Hypothyroxinemia). From the estimates made above from the NAS Committee’s 

hypothyroidism statement, the %TIU(Hypothyroidism) is estimated to occur in range from 6.7% to 

20%, with the low teens being most probable (i.e., 13.3%). The %TIU(Hypothyroxinemia) in women is 

22.7% and is above the NAS Committee’s TIU(Hypothyroidism) of the low teens. The calculation of 

%TIU(Hypothyroxinemia) for hypothyroxinemia in women was performed to corroborate the results 

from Tonacchera Model; the Tonacchera Model results are consistent with information from 

other sources (e.g., the clinical observations from the NAS experts). 

Furthermore, the %TIU(Hypothyroxinemia) in women is 22.7% and is above the 

%TIU(Hypothyroxinemia) found in men of 18.0% to 21.8%. This finding is consistent with the 

observation that women are more sensitive to adverse thyroid effects than men. In the original 

Whickman survey, the rate of high serum TSH concentrations was higher in women than men in 

each decade of age (Vanderpump 2005, p 401, figure 19.2). Furthermore, both the original 

Whickman survey and the subsequent 20-year follow-up survey found the rate of goiter is higher 

in women than men (Vanderpump 2005, p 403). 

9.1.4 Perchlorate PBPK Model and the Greer Perchlorate Exposure Study 

The Tonacchera Model, as with any environmental model, must be corroborated with 

other independent sources of information (EPA 2003a). The Tonacchera Model can be used to 

calculate the TIU at various external doses of perchlorate. The Tonacchera Model uses the 

Clewell Perchlorate PBBK Model to convert external perchlorate doses into internal perchlorate 

doses in the blood serum. As such, the Tonacchera Model is an example of the NAS Toxicity 

Testing Committee’s (NAS 2007) quantitative, mechanistic, dose-response model of the cellular 

138
 
 

 

 

 

 

 

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pathway that is perturbed by the environmental agent. The Clewell perchlorate PBPK model is 

the subsequent pharmacokinetic model called on by the NAS Toxicity Testing Committee to 

convert the internal exposure dose at the cell (i.e., in this case, the perchlorate serum 

concentration in μg/L) to an external exposure dose (i.e., how much is consumed – mg/kg-day). 

As seen in the Clewell perchlorate PBPK model, the conversion factor from internal to external 

perchlorate dose is not constant, but changes due to biological differences across life stages (i.e., 

adult, fetus, neonate, child, pregnant woman, lactating woman) and changes with external 

exposure levels (Clewell 2007, p 423, table 4). Therefore, the calculated TIUs will be slightly 

different for each life stage and external dose level. 

The %TIUs calculated by the Tonacchera Model will be compared against the published 

predicted %TIUs from the Clewell Perchlorate PBBK Model and the %TIUs observed in the 

Greer study. Since, the Greer study was of adults, this comparison of %TIUs is only for adults 

and not for the other life stages. The Clewell perchlorate PBPK model predicted the percentage 

inhibition of TIU across various life stages (Clewell 2007, p 423, table 5). The Greer study 

calculated a 24-hour TIU from the difference in the amount of RAIU from before and after 14 

days of a known external perchlorate exposure at four different levels (Greer 2002, p 931, table 

1, 24-hr uptake). 

The TIUs calculated by the Tonacchera Model at various external perchlorate doses are 

provided in the next two tables (see below). Below is an example of the TIU calculations used to 

populate the values in each of the columns in the next two tables. The resulting internal 

perchlorate dose (i.e., perchlorate serum concentration) in an adult is calculated for an external 

perchlorate dose of 0.001 mg/kg-day using the Clewell perchlorate PBPK model (Clewell 2007, 

p 423, table 4) in the following calculation: 

Int. ClO4

- Dose(Adult) = 0.001 mg x 0.002 mg/L Int. ClO4- Dose = 0.002 mg/L

 kg-day 0.001 mg/kg-day Ext. ClO4

- Dose 

The units of the internal perchlorate dose are converted from mg/L to μmol/L using the 

following calculation: 

Internal ClO4

- Dose(Adult) = 0.002 mg/L x 1000 μg x 1 μmole = 0.020 μmol/L 

 1 mg 99.45 μg 

The SPEC of an internal perchlorate dose of 0.020 μmol/L is calculated using the following 

SPEC equation adapted from the Tonacchera Model (typical U.S. exposures for nitrate and 

thiocyanate are used in for this calculation): 

SPEC(Ext. Per. Dose) = (ClO4

- Inhibition) + (NO3-

 Inhibition) + (free SCN- Inhibition) 

= [ClO4

-

] + [NO3

-

] /240 + ([total serum SCN-] x 0.528) /15 

 = 0.020 μmol/L + (40 μmol/L ÷ 240) + (40 μmol/L x 0.5 free SCN- ÷ 15) 

 = 0.020 μmol/L + 0.167 μmol/L + 1.33 μmol/L 

= 1.52 μmol/L 

139
 
 

 

 

 

 

 

 

 

 

10-P-0101 

The TIU for this external perchlorate dose is calculated using the following Tonacchera Model 

equation: 

TIU(Ext. perchlorate dose) || x_____ _

 (1.22 + SPEC(Ext. perchlorate dose)) 

|| x_____ _ 

(1.22 + 1.52 μmol/L) 

|| x_

 2.74 

|| 0.3650x
 

The %TIU for this external perchlorate dose is calculated using the following equation: 

%TIU(Ext. perchlorate dose) = TIU(Ext. perchlorate dose) ÷ TIU(U.S. normal) x 100% 

= (0.3650x ÷ 0.3675x) x 100% 

 = 99.3% 

The following table provides the TIUs calculated by the Tonacchera Model at various 

external perchlorate doses (see sample calculations above to see how the values were determined 

for each column): 

External ClO4 

-

Dose 

(mg/kg-day) 

Internal ClO4 

-

Dose In an 

Adult 

(mg/L serum) 

Internal ClO4 

-

Dose In an 

Adult 

(μmol/L) 

Serum Perchlorate 

Equivalent Conc. 

(SPEC) 

(μmol/L) 

Calculated Total 

Iodide Uptake 

(TIU) 

0 0.00013 * 0.0013 1.501† 0.3675x 

0.000175 (1⁄4 RfD) 0.00035 0.0035 1.505 0.3670x 

0.0007 (RfD) 0.0014 0.014 1.511 0.3662x 

0.001 0.002 0.020 1.52 0.3650x 

0.007 (NOEL) 0.0088** 0.088 1.589 0.3560x 

0.01 0.01 0.1 1.60 0.3546x 

0.02 0.02 0.2 1.70 0.3325x 

0.1 0.1 1.0 2.50 0.2688x 

0.5 0.5 5.0 6.50 0.1295x 

1.0 1.0 10.0 11.50 0.0786x 

* Median perchlorate exposure in U.S. population (Blount 2006a). 

† From median NIS inhibitor exposures in the U.S. population (calculated in a previous section). 

** Used an estimated conversion factor of 0.009375 mg/L per .0075 mg/kg-day using a linear interpolation from the 

Clewell perchlorate PBPK model. 

The following table provides the %TIUs calculated by the Tonacchera Model at various 

external perchlorate doses and compares them against the published predicted %TIUs from the 

Clewell Perchlorate PBBK Model and the %TIUs observed in the Greer study: 

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10-P-0101 

External 

ClO4 

-

Dose 

(mg/kg-day) 

Calculated Total 

Iodide Uptake 

(TIU) 

%TIU Calculated 

from the 

Tonacchera Model 

%TIU Predicted by 

the Clewell 

Perchlorate 

PBPK Model* 

%TIU 

Measured in 

the 

Greer Study† 

0 0.3675x 100 - -

0.000175 0.3670 99.9 - -

0.0007 0.3662x 99.6 - ClO4 

-

RfD 

0.001 0.3650x 99.3 99.4 -

0.007 0.3560x 96.9 -

98.3 ± 8.3 

(NOEL) 

0.01 0.3546x 96.5 96 -

0.02 0.3325x 93.2 - 83.6 ± 4.1 

0.1 0.2688x 73.1 71 55.3 ± 3.9 

0.5 0.1295x 35.2 - 32.9 ± 3.8 

1.0 0.0786x 21.3 19 -

* Source: Clewell 2007, p 423, table 5. 

† Source: Greer 2002, p 931, table 1, 24-hr uptake. 

In an adult, the Tonacchera Model calculated a 99.6 %TIU at the perchlorate RfD of 

0.0007 mg/kg-day, which corresponds to a 24.5 ppb DWEL. The Tonacchera Model also 

calculated a 99.9 %TIU at 1⁄4 the perchlorate RfD of 0.0000175 mg/kg-day in an adult which 

corresponds to a 6.1 ppb DWEL. Therefore, the Tonacchera Model estimated a 0.3% reduction 

in the TIU when the DWEL is lowered from 24.5 ppb to 6.1 ppb. 

The %TIUs calculated from the Tonacchera Model for an external perchlorate dose for 

0.001, 0.01, 0.1, and 1.0 mg/kg-day are in excellent agreement with the %TIU predicted by the 

Clewell perchlorate PBPK model (see table above). This is expected because the %TIU 

calculation from the Tonacchera Model uses the Clewell perchlorate PBPK model to convert an 

external perchlorate dose to an internal perchlorate dose. Although the %TIUs calculated from 

the Tonacchera Model agree with the %TIUs predicted by the Clewell perchlorate PBPK model, 

this corroboration of results is not a robust test of the Tonacchera Model because only one 

stressor (i.e., perchlorate) is varied, while the other three stressors (i.e., lack of iodide, 

thiocyanate, and nitrate) are held constant. 

The %TIUs calculated from the Tonacchera Model for an external perchlorate dose for 

0.007 and 0.5 mg/kg-day are in excellent agreement with the %TIU observed in the Greer study 

(see table above). However, the %TIUs calculated from the Tonacchera Model for an external 

perchlorate dose for 0.02 and 0.1 mg/kg-day are not in particularly good agreement with the 

%TIU observed in the Greer study (see table above). In short, half of the %TIU values results 

agree, while the other half of %TIU values do not agree well. 

In order to understand the potential sources of differences between the two sets of %TIU 

values, a reexamination of the Greer study data with consideration to all four NIS stressors is 

appropriate. The Greer study calculated a 24-hour TIU from the difference in the amount of 

RAIU from before and after 14 days of a known external perchlorate exposure level. However, 

the Greer study did not attempt to measure or control for the other three known NIS stressors 

(i.e., lack of iodide, thiocyanate, and nitrate). Therefore, the other three known NIS stressors can 

act as confounding variables in the Greer study. 

141
 
10-P-0101 

Although the exposures to the other three NIS stressors were not directly measured in the 

Greer study, the amount of change in an individual’s TIU from the other three known NIS 

stressors can be observed in the 24-hour RAIU results (Greer 2002, Figure 2, provided below). 

If the contribution from the other three NIS stressors was negligible, the measured 24-hour 

RAIU should be the same as before exposure (i.e., baseline visit (BV)) and as 15 days post 

exposure (i.e., P15) when there was no additional external perchlorate dose. At each of the four 

external perchlorate doses, the average raw 24-hour % RAIUs before exposure (i.e., BV) and 15 

days post exposure (i.e., P15) was statistically similar (Greer 2002, table 1, 24-hour uptake 

column). However, the raw 24-hour RAIUs before exposure (i.e., BV) and 15 days post 

exposure (i.e., P15) are far from similar for some of the individual test subjects (Greer 2002, 

figure 2). In figure 2 in the Greer study, if the contribution from the other three NIS stressors 

was negligible to an individual’s TIU, the graphs should be mirror images around exposure day 

14 (E14) and the graphs should not have any crossing lines. However, this is not shown in figure 

2 of the Greer study. 

Source: Greer 2002, figure 2. 

The following table summarizes some of the larger %TIU changes observed in several of 

the individual test subjects that occurred in the 29 days between the BV and the post 15 days 

exposure (P15): 

142
 
 

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External ClO4 

-

Dose 

(mg/kg-day) 

Example 

Test Subject 

Estimated Raw 

RAIU at Baseline 

Visit* 

Estimated Raw 

RAIU at Post 15 

Days* 

Individual %TIU 

change over the 

29 days 

0.007 (fig. 2 d) Purple ‘□’ 34 30 12% decrease 

0.007 (fig. 2 d) Blue ‘◊’ 10 14 40% increase 

0.02 (fig. 2 c) Purple ‘◊’ 18 14 22% decrease 

0.02 (fig. 2 c) Blue ‘◊’ 14 19 29% increase 

0.1 (fig. 2 b) Black ‘*’ 17 29 70% increase 

0.1 (fig. 2 b) Red ‘○’ 19 14 26% decrease 

0.5 (fig. 2 a) Red ‘○’ 33 21 36% decrease 

0.5 (fig. 2 a) Purple‘◊’ 18 30 67% increase 

* The raw numerical RAIU data for individuals were not provided in the published Greer study, but were estimated 

from Greer figure 2 (provide above). 

The point of identifying these large changes in %TIU of individual subjects in the Greer 

study is to highlight that a single chemical risk assessment (i.e., perchlorate only) can seriously 

distort the perception of risk from perchlorate when the other NIS stressors are not considered. 

The Greer study is designed to quantify the amount of perchlorate exposure that causes no 

statistically significant change in the RAIU between before perchlorate exposure and during 

perchlorate exposure, to identify the NOEL for perchlorate. Then, a UF of 10 was applied by the 

NAS Committee to derive the perchlorate RfD to ensure perchlorate exposure at the RfD does 

not cause a significant change (i.e., < 0.2 %TIU) in an individual’s TIU to be protective. 

However, these large changes in %TIU of individual subjects in the Greer study are occurring at 

each exposure dose without any apparent adverse thyroid effects. A perchlorate-only chemical 

risk assessment does not attempt to explain how these large changes in %TIU are occurring in 

the population and does not attempt to identify the source(s) of the effect. If the perchlorate-only 

chemical risk assessment considers a 1.7 %TIU to be potentially risky, why should the potential 

risk inherent in double-digit percentage changes in the %TIU observed in the Greer study 

population be ignored, overlooked, or discounted? 

Fortunately, a cumulative risk assessment approach incorporates the risk from the 

background exposure to all four NIS stressors because the exclusion of one or more stressor(s) or 

the background exposure from a stressor(s) will seriously distort the portion of the total 

estimated risk attributed to perchlorate (i.e., the principal stressor of concern) (EPA 2003, 

appendix C). Furthermore, a cumulative risk assessment distinguishes between background 

exposures and source-specific exposures to provide a more complete picture of both total and 

source-related risks (EPA 2003, appendix C). A cumulative risk assessment identifies the 

amount of risk from the exposure levels observed for each stressor. In regard to this public 

health issue, the Tonacchera Model identifies the lack of iodide in the diet as the dominant 

stressor. When the contribution of iodide is not quantitatively factored into the risk assessment 

(i.e., as in a single chemical assessments done for perchlorate), the result is seriously distorted. 

The Greer study measured the RAIU in 37 test subjects at the start of the study and 

named this RAIU measurement the BV. The observed raw 24-hour RAIU at the BV was 9.8% 

to 33.7%. Therefore, prior to perchlorate exposure, the 24-hour RAIU varied by a factor of 

about 3.4 times. The BV results capture the range in %TIUs found in the study’s population. 

143
 
10-P-0101 

The median 24-hour RAIU at the BV is estimated to be 21.75%. Assigning this as the typical 

RAIU in the population, the range in %TIUs in the study’s population is then estimated to range 

from 45% to 155% of normal (i.e., 100% is nominal). The Greer BV data show that the TIU is 

varying ± 55% in the study population prior to perchlorate exposure without adversely effecting 

thyroid hormone levels. The fT4, tT4, tT3, and TSH levels were measured at BV and were all 

found to be in the normal range prior to and after the experiment (Greer 2002, table 4). 

To manage the risk affecting this public health issue, the 45-155% range in %TIUs of the 

Greer study’s population needs to be understood and explained. The Greer study does not 

explain this observation. However, the Tonacchera Model provides insight into this observation 

by quantifying the TIU contribution from each of the stressors. For example, if all the variations 

in %TIUs in the Greer study population were from variations in the iodide nutritional status, the 

Greer study population would be expected to have a UIC in the range of 65 μg/L and 225 μg/L. 

Since the NHANE III survey identified the 10th to the 90th percentile UIC in the U.S. population 

to be from 45 μg/L to 386 μg/L, the %TIU range observed in the Greer study population can be 

easily accounted for by the expected variation in iodide nutritional status found in the U.S. 

population. Furthermore, this range in TIU indicates that variation in an individual’s iodide 

exposure during the experiment represents a large uncontrolled confounding variable in the 

measurement of the amount of NIS inhibition from perchlorate in the Greer study. 

The %TIUs calculated from the Tonacchera Model for an external perchlorate dose for 

0.007 and 0.5 mg/kg-day are in excellent agreement with the %TIU observed in the Greer study 

(see table above). However, the %TIUs calculated from the Tonacchera Model for an external 

perchlorate dose for 0.02 and 0.1 mg/kg-day are not in particularly good agreement with the 

%TIU observed in the Greer study. Agreement in the 0.5 mg/kg-day dose makes sense because 

the administered perchlorate dose represents a 333% increase in the NIS inhibition load on the 

body (see table below). Any unbalanced variation in the background exposure levels from the 

other NIS inhibitions (nitrate and thiocyanate) will have a smaller effect on the observed %TIU. 

By contrast, in the other three perchlorate dose levels (i.e., 0.007, 0.02, 0.1 mg/kg-day), the 

administered perchlorate only represents a minor or small fraction of the total NIS inhibition load 

on the body. Any unbalance variation in the background exposure levels from the other NIS 

inhibitions, nitrate and thiocyanate, among the test subjects will have a much larger effect on the 

observed %TIU. And, at all perchlorate exposure levels, the potential unbalanced variation in 

the iodide intake (i.e., the dominant NIS stressor) among the test subjects has largest potential to 

confound the observed %TIU. 

External 

ClO4 

-

Dose 

(mg/kg-day) 

Internal ClO4 

-

Dose in an Adult 

(μmol/L serum) 

Estimated Total SPEC 

in the Greer Study 

(μmol/L)* 

% of Estimated 

Total SPEC 

Contributed by 

ClO4 

-

 Dose 

Estimated Total 

SPEC as a % of 

Normal SPEC 

0.007 0.014 1.511 0.9% 101% 

0.02 0.2 1.70 11.7% 113% 

0.1 1.0 2.50 40% 166% 

0.5 5.0 6.50 76% 

433% 

(i.e., a 333% inc. over 

normal SPEC) 

* Background NIS inhibitor exposure in the U.S. population is estimated at 1.501 μmol/L SPEC (see Section 7.2.1). 

144 
10-P-0101 

According to the Tonacchera Model, these potential confounding factors in the Greer 

study do not invalidate the identification of the NOEL. This is because the Tonacchera Model 

agrees with the Greer study that a perchlorate dose of 0.007 mg/kg-day produces a minimal 

change in the %TIU. The Tonacchera Models estimates a 96.9 %TIU at a perchlorate dose of 

0.007 mg/kg-day. The Greer study measured a 98.3 ± 8.3 %TIU at a perchlorate dose of 0.007 

mg/kg-day. The measured 1.7% reduction in the TIU in the Greer study (Greer 2002, table 1) is 

not statistically different than a 0.0% reduction in the TIU. 

In order to isolate the contribution of perchlorate NIS inhibition on the %TIU, the other 

NIS stressors must also be measured through the course of the experiment. In this experimental 

design, any unbalance variation in the background exposure to the other NIS stressor could be 

mathematically factored out to isolate the only the contribution of perchlorate NIS inhibition on 

the %TIU. Fortunately, the Braverman perchlorate occupational cohort study took 

measurements of all four NIS stressors before and during exposure. This will allow the variation 

in the other NIS stressors to be identified and factored out the confounding variables, if 

necessary. This will be demonstrated in the next section. 

9.1.5 Braverman Perchlorate Occupational Exposure Study 

In the Braverman perchlorate occupational exposure study, workers at an ammonium 

perchlorate production facility in Cedar City, Utah, had the RAIU and all four NIS stressors 

measured preexposure and during exposure (Braverman 2005). The study also measured the 

following thyroid parameters: T4, fT4, T3, TSH, and thyroglobulin (Tg). Measurement of all 

four NIS stressors allows the full application of the Tonacchera Model to the study results. 

In the study, the exposed workers had their serum measured for thiocyanate, nitrate, and 

perchlorate concentrations preexposure and during exposure. During exposure, the exposed 

workers’ mean serum concentrations were 3487.8 μg/L of SCN-, 7926.8 μg/L of NO3

-

, and 838.4 

μg/L of ClO4

-

. Since the Tonacchera Model uses units of μmol/L, the corresponding serum 

concentrations are 60.0 μmol/L of SCN-

, 127.8 μmol/L of NO3

-

, and 8.43 μmol/L of ClO4

-

. 

Using these values, the SPEC(During exposure) of the exposed workers can be calculated as follows: 

SPEC(During exposure) = [ClO4

-

] + [NO3

-

] /240 + [free SCN-] /15 

SPEC(During exposure) = 8.43 μmol/L + (127.8 μmol/L ÷ 240) + (60.0 μmol/L x 0.5 free SCN- ÷ 15) 

SPEC(During exposure) = 8.43 μmol/L + 0.53 μmol/L + 2.00 μmol/L 

SPEC(During exposure) = 10.96 μmol/L 

The exposed workers were measured to have a median urinary iodide to creatinine ratio 

of 174 μg I/g creatinine and an average age of 33.6 years (Braverman 2005, table 3). The 

NHANES III survey identified the median urinary iodide to creatinine ratio of 30- to 39-yearolds to be 108.3 μg I/g creatinine (i.e., the normal iodide excretion level for this age group) 

(Hollowell 1998, table 2). Therefore, the perchlorate-exposed workers had a 1.61 times greater 

urinary excretion than the median urinary excretion of the 30- to 39-year-olds in the NHANES 

III survey. The following calculation determines the exposed workers %TIU(During exposure) 36% 

using the TIU(normal) of 0.3675x as the baseline: 

145
 
 

 

 

 

 

 

 

10-P-0101 

Inserting10.96 μmol/L for SPEC(During exposure) and 1.61x for the [I-](During exposure) into the 

Tonacchera Model gives: 

TIU(During exposure) || [I-

](Exposed workers) _ 

(1.22 + SPEC(Exposed workers)) 

TIU(During exposure) || 1.61x _ 

(1.22 + 10.96 μmol/L) 

TIU(During exposure) || 0.1322x 

The %TIU(During exposure) in the exposed is calculated using the following equation: 

%TIU(During exposure) = (TIU(During exposure) ÷ TIU(Normal)) x 100% 

%TIU(During exposure) = (0.1322x ÷ 0.3675x) x 100% 

%TIU(During exposure) = 36.0 % 

The Braverman study reports a mean RAIU(During exposure) of 13.5 % ± 7.1% and a mean 

RAIU(Preexposure) of 21.5 % ± 8.2%. The study determined that the perchlorate exposure in the 

workers resulted in an average 38% decrease in RAIU (i.e., 38% NIS inhibition) during exposure 

as compared to the workers’ preexposure baseline. The corresponding %TIU for comparison is 

calculated as: 1 - (13.5% ÷ 21.5%) x 100% = 62.8%. At first glance, the Tonacchera Model 

calculated %TIU(During exposure) of 36.0 % does not agree with the measured %TIU in the study of 

62.8%. However, these two %TIU values cannot be compared directly because of the following 

two reasons: 

•	 The %TIU values are calculated from different TIU baselines. The Tonacchera 

Model used a TIU(Normal) of 0.3675x as the baseline, which was calculated from the 

typical U.S. exposure to the four NIS stressors. The %TIU from the Braverman study 

used the TIU from the workers’ preexposure as the baseline. The TIU(Preexposure) is 

calculated as 0.3370x, which represents a higher NIS stress level than the typical NIS 

stress level of 0.3675x. Since all four NIS stressors were measured, the TIU(Preexposure) 

can be calculated and the raw RAIU(Preexposure) value can be normalized to the NIS 

stressor condition at the TIU(Normal) for the comparison. 

•	 Since the TIU(During exposure) is the integrated effect from combined exposure to all four 

NIS stressors, to measure only the NIS inhibition from perchlorate requires the 

exposure from the other three NIS stressors to remain constant. However, the 

TIU(During exposure) is confounded by a substantial change in the median urinary iodide 

to creatinine ratio between during exposure and during preexposure (i.e., the iodide 

stressor will be shown to be the dominant stressor in this public health issue). The 

median urinary iodide to creatinine ratio was 174 μg I/g creatinine during exposure 

and 133 μg I/g creatinine at preexposure. By contrast, the mean thiocyanate serum 

concentrations during exposure and preexposure are essentially the same at 7926.8 

146
 
 

 

 

 

 

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μg/L and 7638.6 μg/L, respectively (i.e., 2.00 μmol/L SPEC vs 1.90 μmol/L SPEC). 

Likewise, the mean nitrate serum concentrations during exposure and preexposure are 

essentially the same at 3487.8 μg/L and 3304.0 μg/L, respectively (i.e., 0.53 μmol/L 

SPEC vs 0.51 μmol/L SPEC). Since all four NIS stressors were measured, the 

difference in urinary iodide between preexposure and during exposure can be factored 

out of the TIU(During exposure). Since all four NIS stressors were measured, the 

TIU(Preexposure) can be calculated and the raw RAIU(Preexposure) value can be normalized 

to the TIU(Normal) for the comparison. 

The TIU(Preexposure) can be calculated, but the SPEC(Preexposure) must be calculated first. 

During exposure, the exposed workers’ mean serum concentrations during the preexposure were 

measured to be 3304.0 μg/L of SCN-

, 7638.6 μg/L of NO3

-

, and 2.0 μg/L of ClO4

-

. Since the 

Tonacchera Model uses units of μmol/L, the corresponding serum concentrations are 56.9 

μmol/L of SCN-

, 123.2 μmol/L of NO3

-

, and 0.02 μmol/L of ClO4

-

. Using these values, the 

SPEC(Preexposure) of the exposed workers can be calculated as follows: 

SPEC(Preexposure) = [ClO4

-

] + [NO3

-

] /240 + [free SCN-] /15 

SPEC(Preexposure) = 0.02 μmol/L + (123.2 μmol/L ÷ 240) + (56.9 μmol/L x 0.5 free SCN- ÷ 15) 

SPEC(Preexposure) = 0.02 μmol/L + 0.51 μmol/L + 1.90 μmol/L 

SPEC(Preexposure) = 2.43 μmol/L 

The exposed workers at preexposure were measured to have a median urinary iodide to 

creatinine ratio of 133 μg I/g creatinine and an average age of 33.6 years old (Braverman 2005, 

table 3). The NHANES III survey identified the median urinary iodide to creatinine ratio of 30­

to 39-year-olds to be 108.3 μg I/g creatinine (i.e., the normal iodide excretion level for this age 

group) (Hollowell 1998, table 2). Therefore, the exposed workers at preexposure had a 1.23 

times greater urinary excretion than the median urinary excretion of the 30- to 39-year-olds in 

the NHANES III survey. The following calculation determines the exposed workers’ 

%TIU(Preexposure): 

Inserting 2.43 μmol/L for SPEC(Preexposure) and 1.23x for the [I-

](Preexposure) into the 

Tonacchera Model gives: 

TIU(Preexposure) || [I-

](Preexposure)_ ____ 

(1.22 + SPEC(Preexposure)) 

TIU(Preexposure) || 1.23x_ ____ 

(1.22 + 2.43 μmol/L) 

TIU(Preexposure) || 0.3370x 

The TIU(Preexposure) of 0.3370x is less than the TIU(Normal) of 0.3675x. Therefore, the 

TIU(Preexposure) value is only 0.917 of TIU(Normal) (i.e., 0.3370x ÷ 0.3675x). In other words, the 

four NIS stressors at preexposure is a slightly more stressful NIS condition than the typical 

exposure to the four NIS stressors found in the U.S. population. The raw RAIU(Preexposure) of 

21.5% is multiplied by a factor of 1.09 (i.e., 1/0.917) to estimate what the RAIU(Preexposure) would 

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have been if preexposure was under the typical NIS stressor exposure conditions found in the 

U.S. population (i.e., a UIC of 145 μg/L and a SPEC(Normal) of 1.501 μmol/L SPEC). Thus, to 

normalize the raw RAIU(Preexposure) for a common baseline of comparison to the Tonacchera 

Model, the normalized RAIU(Preexposure) is calculated as follows: 

normalized RAIU(Preexposure) = raw RAIU(Preexposure) x (1/0.917) 

normalized RAIU(Preexposure) = 21.5% x (1/0.917) 

normalized RAIU(Preexposure) = 23.4 % 

The difference in urinary iodide between preexposure and during exposure can be 

factored out of the raw RAIU(During exposure). The exposed workers were measured to have a 

median urinary iodide to creatinine ratio of 174 μg I/g creatinine. The median urinary iodide to 

creatinine ratio was 133 μg I/g creatinine at the preexposure. Therefore, the median urinary 

iodide to creatinine ratio during exposure was 1.30 times greater than at preexposure. The raw 

RAIU(During exposure) must be reduced by a factor of 0.764 to factor out the increased TIU 

contributed by the higher intake of iodide during exposure. Therefore, the adjusted RAIU(During 

exposure) represents the RAIU caused by only the increase in perchlorate exposure, while the other 

three NIS stressors are either essentially the same (i.e., thiocyanate and nitrate) or factored out 

(i.e., as in iodide). The adjusted RAIU(During exposure) is calculated as follows: 

 adjusted RAIU(During exposure) = raw RAIU(preexposure) x (1/1.30) 

 adjusted RAIU(During exposure) = 13.5% x 0.764 

 adjusted RAIU(During exposure) = 10.3% 

Therefore, the normalized %TIU(During exposure) for comparison to the Tonacchera Model 

calculated %TIU(During Exposure) of 36.0 % is calculated as follows: 

Normalized %TIU(During exposure) = adj. RAIU(During exposure) ÷ normalized RAIU(preexposure) x 100% 

Normalized %TIU(During exposure) = (10.3% ÷ 23.4%) x 100%
 

Normalized %TIU(During exposure) = 44% (i.e., a 56% NIS inhibition)
 

After factoring out the differences in baselines and iodide exposures, the normalized 

%TIU(During exposure) of 44% compares favorable with the Tonacchera Model calculated 

%TIU(During exposure) of 36.0 %. The standard deviations in the raw RAIU measurements in the 

Braverman study were greater than 38% of the measured RAIU value for both during exposure 

and preexposure. This means the difference in the normalized %TIU(During exposure) and the 

Tonacchera Model calculated %TIU(During exposure) is well within the statistical variation of the 

RAIU measurement. 

9.1.6 Qualitative Risk Assessment of NIS Stressors 

In 2003, EPA’s Framework for Cumulative Risk Assessment identified that a cumulative 

risk assessment considers the joint impact of multiple stressors. In Section 3.2.2.1, the 

Framework for Cumulative Risk Assessment states, “Studies on individual stressors can, 

however, provide informative qualitative information for multistressor assessments, particularly 

regarding hazard identification” (EPA 2003, p 44). Since adverse health effects have not been 

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clearly demonstrated in any human population exposed to perchlorate (NAS 2005, p 177), the 

potential human response to NIS inhibition from perchlorate exposure can be studied by 

qualitatively evaluating the human response to exposure to the other NIS inhibitors, such as 

thiocyanate. Therefore, the human biological response to the NIS inhibition from thiocyanate 

provides insight into the potential human response to other NIS inhibitors, such as perchlorate. 

Insight into the Toxicity of NIS Inhibition through the Qualitative Review of 

Endemic Cretinism 

Endemic cretinism is the irreversible severe impairment of intellectual and physical 

development (Delange 2005a, p 731). In both neurologic cretinism and myxedematous 

cretinism, cretins are severely mentally retarded. Endemic cretinism occurs in 5-15% of severe 

goiter populations. Endemic cretinism constitutes the extreme expression of the spectrum of 

abnormalities in physical and intellectual development from iodide deficiency (i.e., a low 

maternal %TIU) during gestation. Iodide deficiency is the principal factor in the etiology of 

endemic cretinism. The degree of iodide deficiency correlates with the frequency of cretinism. 

Since the level of iodide deficiency is an indirect measure of TIU level, the degree of maternal 

TIU correlates with the frequency of cretinism. A low TIU during pregnancy is the same 

mechanism of toxicity as perchlorate. Thus, endemic cretinism occurs through the same 

mechanism of toxicity as perchlorate and represents a case study with which to qualitatively 

evaluate the factors influencing the toxicity of NIS inhibition. The main difference between 

endemic cretinism and the public risk from excess NIS stressor exposure in the United States is 

that both the severity of the maternal %TIU and the severity of the resulting mental deficits are 

less in the United States. 

Iodide deficiency is the main factor in the etiology of endemic cretinism (Delange 2005a, 

p 734). Delange makes this conclusion based on the following: 

1.	 The degree of iodide deficiency correlates with the frequency of cretinism 

2.	 The prophylactic action of iodide in preventing endemic cretinism (i.e., correcting iodide 

deficiency). 

3.	 Cretinism has emerged in previously unaffected populations in the Jimi Valley of New 

Guinea, due to the recent onset of iodide deficiency when the local, iodide-rich rock salt 

was replaced with low-iodide industrial salt. 

Naturally occurring goitrogens in the diet are also a factor in the etiology of endemic 

cretinism (Delange 2005a, p 735). Cassava is a staple food in tropical areas. Cassava contains 

cyanogenic glucosides. Upon ingestion, the cyanogenic glucosides in cassava are hydrolyzed 

into cyanide, which is subsequently metabolized by the body into thiocyanate. Thiocyanate is a 

potent NIS inhibitor. However, dietary intake of thiocyanate from properly prepared cassava is 

not sufficient to induce endemic cretinism alone (i.e., NIS inhibition from thiocyanate is not as 

strong a factor as iodide deficiency), but thiocyanate NIS inhibition works in conjunction with 

iodide deficiency to induce endemic cretinism. In other words, the role of thiocyanate on 

endemic cretinism is entirely due to the aggravation of iodide deficiency (Delange 2005a, p 735). 

The toxicity of thiocyanate is not fixed, but the critical threshold of inducing endemic cretinism 

from thiocyanate NIS inhibition is related to the dietary intake of iodide (i.e., as measured by 

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UIC). Goiter develops when the UIC-to-thiocyanate ratio falls below the critical threshold of 

about 3 μg of iodide per mg of dietary thiocyanate (Delange 2005, p 267). Therefore, the 

observed toxicity of thiocyanate NIS inhibition is not fixed, but is related to the dietary intake 

level of iodide. 

The lack of selenium is an additional factor in the etiology of endemic cretinism. 

However, selenium deficiency works through a different mechanism of toxicity than goitrogens. 

Since selenium deficiency is believed to be extremely rare in the U.S. population and works 

through a different mechanism of toxicity, this factor is not directly relevant to the perchlorate 

public health issue and, therefore, is not discussed here. 

The role of the NIS inhibition from thiocyanate on endemic cretinism is consistent with 

the risk characterization observed in the OIG’s cumulative risk assessment of NIS inhibition on 

this public health issue. Endemic cretinism is the extreme example of abnormalities in physical 

and intellectual development from extremely low maternal TIU. However, since the mechanism 

of toxicity of cretinism is the same as that of NIS inhibition from perchlorate, the observed role 

of the risk factors in endemic cretinism can be qualitatively applied to the perchlorate public 

health issue. Specifically, the following observations from the OIG Analysis are consistent with 

the observed role of the risk factors in endemic cretinism: 

•	 The OIG Analysis identifies the lack of iodide stressor (i.e., iodide deficiency) as the 

dominant NIS stressor in inducing a low maternal TIU resulting in increased risk of 

subtle mental deficits in the children. This risk characterization is consistent with the 

dominant role that iodide deficiency has in endemic cretinism. 

•	 The OIG Analysis identifies that the thiocyanate NIS stressor has a smaller impact on 

lowering TIU than does the lack of iodide stressor. This risk characterization is 

consistent with the observation that thiocyanate NIS inhibition from cassava 

consumption is not sufficient by itself to induce endemic cretinism, which makes 

thiocyanate NIS inhibition only a contributing factor on the etiology of endemic 

cretinism. 

•	 The OIG Analysis identifies that the amount of NIS inhibition from the typical range of 

thiocyanate exposure in the United States in iodide-sufficient individuals (i.e., UIC 

greater or equal to 145 μg/L) is not sufficient to lower maternal TIU enough to increase 

the risk of subtle mental deficits in her child. However, the amount of NIS inhibition 

from the typical range of thiocyanate exposure in the United States, in conjunction with 

iodide deficiency (i.e., UIC less than or equal to 100 μg/L), is sufficient to lower 

maternal TIU enough to increase the risk of subtle mental deficits in her child. This risk 

characterization is consistent with and parallels the observation that thiocyanate NIS 

inhibition from cassava consumption is not sufficient by itself to induce endemic 

cretinism, but works in conjunction with iodide deficiency to induce endemic cretinism. 

•	 The OIG Analysis identifies that the toxicity of NIS inhibition is not fixed, but the 

body’s ability to tolerate NIS inhibition is directly related to the iodide nutrition level. 

This risk characterization is consistent with the clinical observations in endemic goiter 

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regions where the toxicity of thiocyanate NIS inhibition from cassava consumption is not 

fixed, but has a critical threshold ratio related to the dietary iodide intake level (i.e., 3 μg 

of dietary iodide per mg of thiocyanate). 

•	 The OIG Analysis identifies that the lack of iodide (i.e., iodide deficiency) during 

pregnancy (i.e., UIC less than or equal to 100 μg/L) is the major factor increasing the 

risk of permanent subtle mental deficits in children. The OIG Analysis identified that 

the most effective and efficient approach to correcting this public health issue of low 

maternal TIU during pregnancy and nursing is to add iodide to all prenatal vitamins and 

to ingest them before and during pregnancy and nursing. This risk characterization is 

consistent with the clinical observations in endemic goiter populations where endemic 

cretinism is prevented by correcting iodide deficiency through the injection of iodized oil 

(Delange 2005a, p 741-42), (i.e., correcting low maternal TIU). 

Therefore, the qualitative evaluation of the roles of iodide deficiency and NIS inhibition in the etiology 

of endemic cretinism are consistent with the cumulative risk characterization of this public health issue 

posed by the potential for inducing low maternal TIU from excessive NIS inhibitor exposure. 

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9.2 Assessing the Contribution of Each NIS Stressor on the TIU 

9.2.1 Evaluation of the Amount of NIS Inhibition Contributed by Each NIS 

Inhibitor 

A critical aspect of a cumulative risk assessment is to incorporate the risk from the 

background exposure to the stressors because the exclusion of a stressor(s) or the background 

exposure from a stressor(s) “may seriously distort” the portion of the total estimated risk 

attributed to the principal stressor of concern (EPA 2003, appendix C). Cumulative risk 

assessment distinguishes between background exposures and source-specific exposures to 

provide a more complete picture of both total and source-related risks (EPA 2003, appendix C). 

As shown by the Tonacchera experiment used to derive the Tonacchera Model, the three NIS 

inhibitors, thiocyanate, nitrate, and perchlorate, act together to inhibit the uptake of iodide by the 

NIS (Tonacchera 2004). The inhibition of the NIS by thiocyanate, nitrate, and perchlorate is 

“indistinguishable” from a concentration or dilution of each other (Tonacchera 2004). Therefore, 

the NIS inhibition contribution by perchlorate exposure has to be evaluated in context to the total 

body’s burden of NIS inhibition. 

To address this aspect of a cumulative risk assessment, the typical background exposure 

to thiocyanate and nitrate was estimated in the U.S. population to evaluate the amount of the 

inhibition of the NIS of each NIS inhibitor at various perchlorate exposures. As calculated 

previously in this document, the following table summarizes the results: 

Relative Contribution of Each NIS Inhibitor 

To the Total Amount of NIS Inhibition in an Adult 

Perchlorate 

Exposure Level 

Total Amount of NIS 

Inhibition in an Adult 

(SPEC) Perchlorate 

Nitrate 

at 

(40 μmoles/L) 

Thiocyanate 

at 

(40 μmoles/L) 

At the perchlorate NOEL 

(0.007 mg/kg-day) 1.567 μmoles/L 4.5 % 10.7% 85.1% 

At the perchlorate RfD of 

(0.0007 mg/kg-day) 1.511 μmoles/L 0.93% 11.1% 88.2% 

95th percentile of U.S. 

population (Blount 2006) 1.505 μmoles/L 0.31% 11.1% 88.6% 

50th percentile of U.S. 

population (Blount 2006) 1.501 μmoles/L 0.09% 11.1% 88.8% 

Zero perchlorate 1.500 μmoles/L 0.00% 11.1% 88.9% 

This table clearly shows that when the amount of NIS inhibition from perchlorate 

exposure is evaluated in context to the typical amount of NIS inhibition contributed from the 

routine exposure to thiocyanate and nitrate, the amount of NIS inhibition from perchlorate 

exposure is relatively small. At the perchlorate RfD of 0.007 mg/kg-day in an adult, the amount 

of NIS inhibition from perchlorate exposure is less than 1%. Therefore, as identified in EPA 

guidance, the exclusion of the background exposure to thiocyanate and nitrate in single chemical 

risk assessment “seriously distorts” the portion of the total estimated risk attributed to the 

principal stressor of concern, perchlorate (EPA 2003, appendix C). 

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As indicated by the Tonacchera Model, perchlorate is only one of four stressors that 

contribute to the amount of iodide taken up by the NIS. A thorough cumulative risk assessment 

identifies the exposure levels of the stressors that result in adverse effects. For this public health 

issue, this means that this cumulative risk assessment must identify the level of TIU in pregnant 

women that leads to fetal brain damage. Once the critical level of TIU is identified, then each of 

the four NIS stressors must be managed to prevent the critical TIU level from being exceeded. 

9.2.2 Evaluation of %TIU as a Function of Total NIS Inhibition Load 

The amount of iodide taken up by the thyroid is the integrated effect from the exposure of 

all four NIS stressors. However, the three NIS stressors (thiocyanate, nitrate, and perchlorate) 

are “indistinguishable” from a concentration or dilution of each other (Tonacchera 2004). 

Therefore, their combined NIS inhibitor exposure can be expressed as a single variable reflecting 

the total NIS inhibition load on the body (i.e., SPEC), which is measured in μmol/L SPEC. 

Thus, the Tonacchera Model is simplified into a two-variable equation. This simplification 

allows the TIU to be expressed as a function of the body’s total NIS inhibition load (i.e., SPEC) 

at a given level of iodide nutrition (e.g., normal iodide intake level). Therefore, to examine this 

impact of SPEC on TIU, the iodide is held constant, but the SPEC is allowed to change. The 

following is an example calculation: 

The Tonacchera Model stated as a two-variable equation: 

 TIU || [I-

] / (1.22 + (SPEC)) 

If the [I-

] is held constant (i.e., at a stable iodide nutritional level – “x”), the total NIS 

inhibition exposure level (i.e., SPEC) can be calculated for any given TIU level by using the 

following equation: 

TIU(Normal) x fraction of TIU || x____ _ __

 (1.22 + SPEC(%TIU)) 

Given TIU(Normal) in the U.S. population for an adult is 0.3675x, then solving for 

SPEC(%TIU) becomes 

SPEC(% TIU) || x___ - 1.22 

0.3675x x (fraction of TIU) 

For a TIU level of 25% of normal, the SPEC(25% TIU) becomes 

SPEC(25% TIU) || x___ - 1.22 

0.3675x x (0.25) 

SPEC(25% TIU) || x___ - 1.22 

0.091875x 

SPEC(25% TIU) || 10.88 - 1.22 

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SPEC(25% TIU) || 9.66 

This calculated value estimates that a total goitrogen load of 9.66 μmol/L SPEC at a 

typical U.S. iodide nutritional level will induce the TIU to be lowered to 25% of the normal TIU. 

Since the SPEC(Median) is 1.501 μmol/L, an increased NIS inhibitor exposure amount of 8.16 

μmol/L SPEC, or 544% increase of normal TIU, is needed to lower normal TIU to 25%. Using 

the Tonacchera Model to calculate the values, the following table provides the SPEC(%TIU) for an 

adult at several %TIU levels: 

%TIU Level 

of Normal 

Iodide 

Nutrition 

(%) 

of Normal 

SPEC(%TIU)

(μmol/L) 

Additional SPEC 

Exposure Above U.S. 

Normal* to Achieve TIU 

Level 

(μmol/L) 

Percent Increase 

in Additional NIS Inhibitor 

Load Needed to Generate 

Specified TIU Level 

(%) 

15 100 16.92 15.41 1027 

20 100 12.38 10.88 725 

25 100 9.66 8.16 544 

35 100 6.55 5.05 337 

50 100 4.22 2.72 181 

60 100 3.32 1.81 121 

75 100 2.42 0.92 62 

90 100 1.80 0.30 20 

95 100 1.64 0.14 9.3 

99 100 1.528 0.027 1.8 

100 

(normal TIU) 100 1.501 0 0 

110 100 1.25 -0.25 -16.7 

* U.S. normal SPEC is 1.501 μmol/L (see calculation in Section 7.2.1). 

Source: OIG Analysis; Tonacchera Model calculations. 

This modeling of %TIU as a function of the body’s total NIS inhibition load at normal 

iodide intake shows that the thyroid can tolerate a lot of exposure to NIS inhibitors before 

changes in thyroid hormone production. As observed in the adult males and females in the 

Banerjee thiocyanate studies, hypothyroxinemia is not expected to be observed until %TIU falls 

at or below 22.7% (Banerjee 1997; Banerjee 1997b). Therefore, in an adult with a normal iodide 

intake, the thyroid can tolerate up to an additional 8.16 μmol/L SPEC of NIS inhibition above 

the background NIS inhibition load of 1.501 μmol/L SPEC before adult thyroid is unable to 

maintain T4 production. This represents a 544% increase in the body’s normal total goitrogen 

load. Only under rare exposure conditions to NIS inhibitors does the total goitrogen load 

increase to this point in the Western world (e.g., from occupational exposures or from 

medicines). By comparison, the amount of NIS inhibition contributed by perchlorate at the RfD 

in an adult is only 0.014 μmol/L SPEC (i.e., a 0.9% increase of the normal goitrogen load on the 

body). 

The modeling of %TIU as a function of Total NIS Inhibition Load at a normal iodide 

intake is graphically presented below: 

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Source: OIG Analysis – graphic representation of the table immediately above. 

Since the range of thiocyanate and nitrate exposure in the Western world is known, the 

upper range for the total NIS inhibition load in the Western world can be calculated for both 

smokers and nonsmokers using the Tonacchera Model. The total NIS inhibition load is 

separated into smokers and nonsmokers because the act of smoking is a significant source of 

cyanide, which is subsequently metabolized into the NIS inhibitor thiocyanate. For nonsmokers, 

the thiocyanate serum concentration is typically in the range of 10-70 μmol/L. By contrast, for 

smokers, the thiocyanate serum concentration is higher and is typically in the range of 80-120 

μmol/L. In the Western world, the typical nitrate serum concentration ranges from 10-140 

μmol/L (Tonacchera 2004). Therefore, the upper range of the total NIS inhibitor load in a 

nonsmoker is then calculated using140 μmol/L for serum nitrate, the70 μmol/L for serum 

thiocyanate, and 0.0047 μmol/L for perchlorate (i.e., the 95th percentile observed in the Blount 

Biomonitoring Study (Blount 2006a (see Section 7.2.1)). Therefore, the SPEC(Upper range nonsmoker) 

is given by the following calculation: 

SPEC (Upper range nonsmoker) = [ClO4

-

] + [NO3

-

] /240 + [free SCN-] /15 

SPEC (Upper range nonsmoker) = 0.0047 μmol/L + (140 μmol/L ÷ 240) + (70 μmol/L x 0.5 free SCN- ÷ 15) 

SPEC (Upper range nonsmoker) = 0.0047 μmol/L + 0.583 μmol/L + 2.333 μmol/L 

SPEC (Upper range nonsmoker) = 2.92 μmol/L 

A nonsmoker with a normal iodide intake exposed to NIS inhibitors at an SPEC (Upper range 

nonsmoker) of 2.92 μmol/L (purple line in the graph above) has a calculated %TIU of 66%. This is 

well above the %TIU associated with hypothyroxinemia or hypothyroidism. Therefore, at a 

normal iodide nutritional level, the upper observed range for total NIS inhibition load in the 

nonsmoking population does not sufficiently decrease the %TIU level to prevent the thyroid 

from adapting and maintaining thyroid hormone production in the normal range. 

Likewise, the upper range of the total NIS inhibitor load in a smoker is then calculated 

using 140 μmol/L for serum nitrate, 120 μmol/L for serum thiocyanate, and 0.0047 μmol/L for 

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perchlorate (i.e., the 95th percentile observed in the Blount biomonitoring study (Blount 2006a 

(see Section 7.2.1)). Therefore, the SPEC(Upper range smoker) is given by the following calculation: 

SPEC (Upper range smoker) = [ClO4

-

] + [NO3

-

] /240 + [free SCN-] /15 

SPEC (Upper range smoker) = 0.0047 μmol/L + (140 μmol/L ÷ 240) + (120 μmol/L x 0.5 free SCN- ÷ 15) 

SPEC (Upper range smoker) = 0.0047 μmol/L + 0.583 μmol/L + 4.000 μmol/L 

SPEC (Upper range smoker) = 4.59 μmol/L 

A smoker with a normal iodide intake exposed to NIS inhibitors at an SPEC (Upper range smoker) of 

4.58 μmol/L (brown line in the graph above) has a calculated %TIU of 47%. This is well above 

the %TIU associated with hypothyroxinemia or hypothyroidism. Therefore, at a normal iodide 

nutritional level, the upper observed range for total NIS inhibition load in the smoking 

population does not sufficiently decrease the %TIU level to prevent the thyroid from adapting 

and maintaining thyroid hormone production in the normal range. 

To summarize, the graph of %TIU as a function of total NIS inhibition load at a normal 

iodide nutrition level identifies that the cumulative effect of all three NIS inhibitors (even at the 

upper range of exposure to each NIS inhibitor found in the U.S. population) does not exceed the 

thyroid’s ability to compensate for the stress. In other words, the largest total NIS inhibition 

loads observed in the U.S. population are insufficient to lower the %TIU below the critical level 

of 22.7% to result in hypothyroxemia. Therefore, this analysis identifies that the essential role 

and contribution of the lack of iodide NIS stressor (i.e., the fourth NIS stressor) is to induce a 

sufficiently low %TIU (i.e., 22.7% in nonpregnant women) to decrease serum T4 levels below 

the normal range. The added stress from the lack of iodide NIS stressor is the critical factor 

affecting this public health issue. An iodide-deficient diet is required to induce a low enough 

%TIU level to result in T3 or T4 serum level below the normal range. 

Perchlorate Occupational Cohort Study 

In the Braverman perchlorate occupational cohort study, the ammonium perchlorate 

workers (i.e., all were males) at Cedar City, Utah, facility had their serum measured for 

thiocyanate, nitrate, and perchlorate (Braverman 2005). The mean serum concentrations during 

exposure were 3487.8 μg/L of SCN-, 7926.8 μg/L of NO3

-

, and 838.4 μg/L of ClO4

-

. Since the 

Tonacchera Model uses units of μmol/L, the corresponding serum concentrations are 60.0 

μmol/L of SCN-

, 127.8 μmol/L of NO3

-

, and 8.43 μmol/L of ClO4

-

. Using these values, the 

SPEC of the exposed workers can be calculated as follows: 

SPEC(Exposed workers) = [ClO4

-

] + [NO3

-

] /240 + [free SCN-] /15 

SPEC(Exposed workers) = 8.43 μmol/L + (127.8 μmol/L ÷ 240) + (60.0 μmol/L x 0.5 free SCN- ÷ 15) 

SPEC(Exposed workers) = 8.43 μmol/L + 0.53 μmol/L + 2.00 μmol/L 

SPEC(Exposed workers) = 10.96 μmol/L 

In reviewing the table above, an adult with a SPEC of 10.96 and normal iodide intake 

would be expected to have %TIU of about 22.3%. This %TIU is barely above the 

%TIU(Hypothyroxinemia) range of 18.0% to 21.8% in the Banerjee adult male thiocyanate study that 

induced a T3 and T4 thyroid hormone deficiency in adult males consistent with severe 

hypothyroxinemia. The calcuated %TIU of 22.3% from a total NIS inhibition load of 10.96 

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μmol/L at a normal iodide nutrition level is in the range in which hypothyroxinemia would be 

expected, but the thyroid hormones in the perchlorate-exposed workers are well within the 

normal range. This is because the TIU integrates the exposure to all four NIS stressors (i.e., not 

just the NIS inhibitors). The iodide stressor is not included in the SPEC value (i.e., the 

calculation held iodide nutritional level at a normal level of 100%). 

If the exposed workers had a normal or below-normal iodide intake, their %TIU would 

be low enough to cause adverse thyroid hormone effects (e.g., hypothyroxinemia). However, the 

exposed workers in the Braverman study were measured to have an median urinary iodide to 

creatinine ratio of 174 μg I/g creatinine and an average age of 33.6 years (Braverman 2005, table 

3). The NHANES III survey identified the median urinary iodide to creatinine ratio of 30- to 39­

year-olds to be 108.3 μg I/g creatinine (i.e., the normal iodide excretion level for this age group) 

(Hollowell 1998, table 2). Therefore, the perchlorate-exposed workers had a 1.61 times greater 

urinary excretion than the median urinary excretion of the 30- to 39-year-olds in the NHANES 

III survey. The following calculation shows that the above-median intake of iodide by the 

exposed workers increased their %TIU from a potentially adverse TIU level of 22.3% to an 

asymptomatic TIU level of 36% (i.e., the increased iodide intake in the exposed workers 

protected them from adverse thyroid effects): 

Inserting 10.96 μmol/L for SPEC(Exposed workers) and 1.61x for the [I-

](Exposed workers) into the 

Tonacchera Model gives: 

TIU(Exposed workers) || [I-

](exposed workers)_____ 

(1.22 + SPEC(Exposed Workers)) 

TIU(Exposed workers) || 1.61x_____ 

(1.22 + 10.96 μmol/L) 

TIU(Exposed workers) || 0.1322x 

The %TIU(Exposed workers) in the exposed is calculated using the following equation: 

%TIU(Exposed workers) = (TIU(Exposed Workers) ÷ TIU(Normal)) x 100% 

%TIU(Exposed workers) = (0.1322x ÷ 0.3675x) x 100% 

%TIU(Exposed workers) = 36.0 % 

An exposed worker with an exposure to NIS inhibitors of SPEC(Exposed worker) of 10.96 μmol/L 

and a iodide intake 1.61 times greater than normal has a calculated %TIU of 36%. This is well 

above the %TIU associated with hypothyroxinemia or hypothyroidism. Therefore, the exposed 

workers in the Braverman study would be expected to have thyroid hormones in the normal range, 

and they were found to have thyroid hormones in the normal range. In other words, the exposed 

workers’ increased iodide intake during exposure protected them from adverse thyroid effects. 

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9.2.3 Evaluation of the Role of Iodide Nutrition on the Ability to Tolerate NIS 

Inhibition 

The Tonacchera Model can also be used to evaluate the impact of iodide nutrition on the 

amount of iodide taken up by the NIS. The three iodide nutrition levels modeled are the 

fractions 0.34, 0.50, and 1.00 of normal which correspond to a UIC of 50 μg/L, 72.5 μg/L, and 

145 μg/L at a SPEC(normal) of 1.501 μmol/L SPEC. The UICs of 50 μg/L, 72.5 μg/L, and 145 

μg/L correspond to borderline moderate iodide deficiency, mild iodide deficiency, and sufficient 

iodide levels. The following table calculates the SPEC(%TIU) for each of the three iodide nutrition 

levels for a given %TIU level (sample calculation not shown, but similar to previous 

calculations): 

%TIU Level 

of Normal 

Iodide 

Nutrition 

Fraction 

of Normal 

SPEC(%TIU)

(μmol/L) 

Additional SPEC 

Exposure 

above U.S. Normal†† 

to Achieve TIU Level 

(μmol/L SPEC) 

Increase in Additional NIS 

Inhibitor Load Needed to 

Generate Specified TIU Level 

(%) 

10 0.34* 8.03 6.53 435 

15 0.34* 4.94 3.45 230 

20 0.34* 3.41 1.90 127 

22.7 0.34* 2.85 1.35 90 

25 0.34* 2.48 0.98 65 

30 0.34* 1.86 0.36 24 

34 0.34* 1.501 0.0 0.0 

10 0.50† 12.38 10.88 725 

15 0.50† 7.85 6.35 423 

20 0.50† 5.58 4.08 272 

22.7 0.50† 4.77 3.27 218 

25 0.50† 4.22 2.72 181 

30 0.50† 3.32 1.81 121 

34 0.50† 2.78 1.28 85 

50 0.50† 1.501 0 0.0 

15 1.00 16.92 15.41 1027 

20 1.00 12.38 10.88 725 

22.7 1.00 10.77 9.27 618 

25 1.00 9.66 8.16 544 

34 1.00 6.78 5.28 352 

50 1.00 4.22 2.72 181 

100 

(normal TIU) 1.00 1.501 0 0.0 

* A 0.34 fraction of iodide nutrition corresponds to borderline moderate iodide deficiency

 (i.e., UIC of 50 μg/L ÷ normal UIC of 145 μg/L in an adult). 

† A 0.50 fraction of iodide nutrition corresponds to mild iodide deficiency 

 (i.e., UIC of 72.5 μg/L ÷ normal UIC of 145 μg/L in an adult). 

†† U.S. normal SPEC is 1.501 μmol/L (see calculation in previous section). 

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The table shows that as iodide nutrition decreases, the thyroid is less able to tolerate a 

large NIS inhibition load. For example, to maintain a %TIU above the asymptomatic %TIU of 

22.7% in an non-pregnant adult, at an iodide nutrition fraction of 1.0, 0.5, and 0.34, the body can 

tolerate up to a total NIS inhibition load on the body of 6.78, 2.78, and 1.501 μmol/L SPEC, 

respectively. An iodide nutrition fraction of 0.34 corresponds to borderline moderate iodide 

deficiency. To summarize, the body’s ability to cope with NIS inhibitors decreases rapidly as 

the iodide intake decreases. 

The modeling of %TIU as a function of total NIS inhibition load at three iodide intake 

levels of 100%, 50%, and 34% is graphically presented below: 

Source: OIG Analysis – graphic representation of the table immediately above. 

This graph demonstrates that the lack of iodide NIS stressor dramatically lowers the 

%TIU level for any given total NIS inhibition load (i.e., shifts the curve to the left). For 

example, decreasing the normal iodide nutrition level in half (i.e., from 100% to 50%) at a 

constant typical total NIS inhibition load proportionally decreases the %TIU in half (i.e., from 

100% to 50%). By contrast, doubling the typical total NIS inhibition load from 1.501 μmol/L 

SPEC to 3.0 μmol/L SPEC at a constant normal iodide nutrition level results in a %TIU of 

64.5% (i.e., a decrease of 35.5%). Therefore, for the NIS stressor exposure conditions in this 

example, the lack of iodide NIS stressor has about 1.4 times the effect as the same amount of 

change in the total NIS inhibition load. This clearly demonstrates that the lack of iodide NIS 

stressor has a larger effect on the %TIU than all the three other NIS stressors combined. 

Therefore, the lack of iodide NIS stressor is the dominant stressor affecting the public health 

issue. 

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As seen in the Banerjee thiocyanate study in male electroplating workers (Banerjee 

1997), a %TIU of about 20% is symptomatic and presents as severe hypothyroxinemia. In this 

study, the low %TIU was brought on by a large total goitrogen load on the thyroid. However, 

since the %TIU is a function of all four NIS stressors, a low %TIU causing the symptoms of 

severe hypothyroxinemia can also be brought on by a borderline moderate iodide deficiency with 

a total goitrogen load found in the upper range of the U.S. population. For example, adult males 

with a 20 %TIU, at iodide nutrition levels of 1.0, 0.5, and 0.34, can tolerate total NIS inhibition 

loads of up to 12.38, 5.58, and 3.41 μmol/L SPEC, respectively. Since the upper range of the 

total NIS inhibition load found in the U.S. population is 4.59 μmol/L SPEC for smokers and 2.92 

μmol/L SPEC for nonsmokers, a portion of only the male smoker subpopulation with borderline 

moderate iodide deficiency (i.e., iodide nutrition fraction of 0.34) with the highest observed 

levels of the total NIS inhibition load would exceed the tolerable limit of 3.41 μmol/L SPEC. 

Therefore, a portion of the borderline moderate iodide-deficient male smokers would be 

expected to show symptoms of hypothyroxinemia. By comparison, borderline moderate iodidedeficient male nonsmokers would not be expected to show symptoms of hypothyroxinemia. 

Furthermore, all the male nonsmokers and the smokers at iodide nutrition factions of 1.0 and 0.5 

would be below the maximum tolerable SPEC values for their iodide nutritional status (i.e., their 

%TIU > 20%). 

As seen in the Banerjee thiocyanate exposure study on females (Banerjee 1997b), a 

%TIU of 22.7% induced hypothyroxinemia in nonpregnant females. In this study, the low %TIU 

was brought on by a large total goitrogen load on the body. However, since the %TIU is a 

function of all four NIS stressors, a low %TIU causing the symptoms of hypothyroxinemia can 

also be brought on by a borderline moderate iodide deficiency with a total NIS inhibition load 

found in the upper range of the U.S. female population. For example, adult females with a 22.7 

%TIU, at iodide nutrition levels of 1.0, 0.5, and 0.34, can tolerate total NIS inhibition loads of up 

to 10.77, 4.77, and 2.85 μmol/L SPEC, respectively. Since the upper range of the total NIS 

inhibition load found in the U.S. population is 4.59 μmol/L SPEC for smokers and 2.92 μmol/L 

SPEC for nonsmokers, both female smokers and nonsmokers with borderline moderate iodide 

deficiency (i.e., iodide nutrition fraction of 0.34) with the highest observed levels of the total NIS 

inhibition load would exceed the tolerable limit of 2.85 μmol/L SPEC. Therefore, a portion of 

the borderline moderate iodide-deficient female smoker and nonsmoker subpopulations would be 

expected to show symptoms of hypothyroxinemia. By comparison, all the female nonsmokers 

and the smokers at iodide nutrition factions of 1.0 and 0.5 would be below the maximum 

tolerable SPEC values for their iodide nutritional status (i.e., their %TIU > 22.7%). 

The clinical observations in areas of endemic cretinism show that the consumption of 

cassava is not the cause of this health problem, but serves to aggravate the underlying problem of 

severe iodide deficiency in these areas (Delange 2005a, p 735). The consumption of cassava 

causes a large NIS inhibition load on the body, but is not large enough to cause health problems 

on its own. Only when the consumption of cassava occurs in conjunction with a low iodide 

intake do health problems occur. The above table and graph express the same finding as that 

observed in the clinical observation in areas of endemic cretinism. In other words, the table and 

graph state that with a healthy iodide intake, the consumption of NIS inhibitors is not large 

enough to induce health problems. However, if iodide intake is low enough, the consumption of 

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moderate amounts of NIS inhibitors can induce health problems; but once again, the root 

problem of the health issue is iodide deficiency, not the moderate consumption of NIS inhibitors. 

The next section also identifies iodide intake as the dominant stressor and quantifies the impact 

on this public health issue. 

In conclusion, the NIS inhibitor exposure levels found in the U.S. population are not 

individually sufficient to induce adverse health effects. However, combined with the added NIS 

stress caused by iodide defiency, the cumulative effect of all four NIS stressors on the TIU by the 

thyroid is sufficient to induce adverse effects in the U.S. population. Therefore, NIS inhibitors 

are not the source of the problem, but act to modulate the toxicity of iodide deficiency. 

9.2.4 Evaluation of the Relative Influence of Each NIS Stressor 

A critical aspect of a cumulative risk assessment is that a stressor does not have to be the 

exposure to a chemical, but the “absence of a necessity” (EPA 2003, p 2). The role of iodide 

nutrition is critical to this public health issue. The Tonacchera Model can be simplified into a 

two-variable equation that establishes the relationship between the amount of iodide and the 

body’s total NIS inhibition load, which is measured in μmol/L SPEC. The following table shows 

the relationship between iodide nutrition and the body’s total NIS inhibition load (a sample 

calculation is not shown, but is similar to previous examples): 

%TIU Level 

of Normal 

Iodide 

Nutrition 

(%) 

of Normal 

SPEC 

(μmol/L) 

Reduction in SPEC Exposure 

From U.S. Normal* to Achieve 

TIU Level 

(μmol/L) 

Percent Change in 

Total NIS Inhibitor Load 

(%)

 99 100 1.528 0.027 1.8 

99 99 1.501 0.0 0.0 

100 

(normal TIU) 100 1.501 0.0 0.0 

100 99.4 1.486 0.015 - 1.0 

100 99 1.474 0.027 - 1.8 

101 100 1.474 0.027 - 1.8 

* U.S. normal SPEC is 1.501 μmol/L (see calculation in previous section). 

This table shows that the lack of iodide stressor is the dominant NIS stressor of the four 

NIS stressors. A 1% decrease in the iodide nutrition level has the same effect as lowering the 

body’s total NIS inhibition load by 1.8%. In short, the lack of iodide stressor has about twice the 

impact on the %TIU as does the impact on the %TIU of all three NIS stressors combined at their 

typical exposure level. Therefore, by not being able to include the nonchemical stressor, lack of 

iodide, the conventional single chemical risk assessments for perchlorate “seriously distort” the 

portion of the total estimated risk attributed to the principal stressor of concern (i.e., perchlorate). 

By implementing a cumulative risk assessment approach, the contribution of the lack of iodide 

stressor is quantitatively factored into the total risk, and the portion of total risk attributed to 

perchlorate and each of the other three NIS stressors can be measured. 

The Tonacchera Model can also be used to quantify the impact on the TIU from each of 

the four NIS stressors. The following table calculates the percent reduction in TIU as a result of 

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a 25% change in the typical concentration of each NIS stressor (a sample calculation is not 

shown, but is similar to previous examples): 

Modeled Condition 

SPEC 

(μmol/L) 

Raw TIU 

Value 

%TIU of Baseline 

at SPEC(RfD) & 

Normal [I-

] 

Reduction in TIU as 

a Result of Modeled 

Condition 

SPEC(RfD) + normal [I-

] 1.511† 0.36617x 100 (baseline) -

SPEC(RfD) + 25% ↓ [I-

] 1.511 0.27463x 75.0 25% 

SPEC(RfD) (25%↑ [ClO4 

-

])* 1.5175 0.36530x 99.8 0.2% 

SPEC(RfD) (25%↑ [NO3 

-

])* 1.5558 0.36026x 98.4 1.6% 

SPEC(RfD) (25%↑ [SCN-

])* 1.8473 0.32602x 89.0 11.0% 

↑ means “increase in” 

↓ means “decrease in” 

* Modeled serum condition is at normal [I-

] 

† Estimated typical total NIS inhibition load at the perchlorate RfD 

Note: The table uses a 25% change in each of the NIS stressors so that the perchlorate effect would be on scale 

(i.e., a fraction of a % change in TIU). 

The table shows the change in %TIU as the result of a 25% change in serum 

concentration of each of the NIS stressors. At the estimated total NIS inhibition load on the body 

at the perchlorate RfD of 1.511 μmol/L SPEC, an isolated 1% change in the serum concentration 

of each of the stressors (i.e., lack of iodide, thiocyanate, nitrate, and perchlorate) induces changes 

in %TIU of 1%, 0.44%, 0.06%, and 0.008% respectively. Therefore, the relative impact of the 

stressors on this public health issue can be described by the following mathematical expression: 

Lack of Iodide > SCN- >> NO3

- >> ClO4­

Where: “ > ” means “greater than” 

 “ >> ” means “much greater than” 

The relative impact of each of the NIS stressors can be described in the following words: 

the lack of iodide (i.e., iodide nutrition) is the dominant stressor (i.e., strongest NIS stressor), 

thiocyanate exposure is a medium-strength stressor, nitrate exposure is a weak NIS stressor, and 

perchlorate exposure is a very weak NIS stressor. The relative impact of each of the NIS 

stressors is useful information when evaluating the course of action to take to effectively address 

this public health issue. 

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9.2.5 Assessing the Effectiveness of Lowering the Total NIS Inhibition Load to 

Compensate for Poor Iodide Nutrition 

The Tonacchera Model can be used to assess the effectiveness of potentially reducing the 

body’s total NIS inhibition load to compensate for poor iodide nutrition to maintain a normal 

TIU level. The following table summaries the modeled results (a sample calculation is not 

shown, but is similar to previous examples): 

Iodide Calculated SPEC 

Nutritional Exposure Reduction in SPEC Percentage 

TIU Level Level Required to Maintain Exposure Needed to Reduction in 

(%) Fraction Normal TIU level Maintain Normal TIU Level SPEC Exposure 

of Normal of Normal (μmol/L) (μmol/L) (%) 

100 1.00 1.501* 0 0 

100 0.99 1.474 0.027 1.8 

100 0.98 1.447 0.054 3.6 

100 0.95 1.365 0.136 9.1 

100 0.935 1.324 0.176 11.8 

100 0.90 1.229 0.272 18.1 

100 0.75 0.821 0.680 45.3 

100 0.69 0.657 0.843 56.2 

100 0.50 0.140 1.361 90.7 

* 1.501 μmol/L SPEC is the baseline amount of total NIS inhibition acting on the body. 

The table shows that reducing the total NIS inhibition load acting on the body is neither 

practical nor biologically achievable approach for compensating for poor iodide nutrition. A 1% 

decrease in the iodide nutritional level (i.e., corresponds to a mean UIC of 143.6 μg/L) can be 

offset by decreasing the body’s total NIS inhibition load by 0.027 μmol/L SPEC. By 

comparison, the amount of NIS inhibition in an adult contributed by perchlorate at the RfD to the 

body’s total NIS inhibition load is only 0.014 μmol/L SPEC. 

Likewise, the table shows that a 7.5% decrease in the iodide nutritional level (i.e., 

corresponds to a mean UIC of 136 μg/L) can be offset by decreasing the body’s total NIS 

inhibition load by 0.176 μmol/L SPEC. By comparison, the amount of NIS inhibition 

contributed by both perchlorate exposure at the RfD and the typical nitrate exposure in an adult 

is only 0.181 μmol/L SPEC. So, all exposure to perchlorate at the RfD and nitrate would have to 

be eliminated to offset a 7.5% decrease in the body’s intake of iodide. 

Furthermore, the table shows that a 31% decrease in the iodide nutritional level to 

borderline mild iodide deficiency (i.e., corresponds to a mean UIC of 100 μg/L) can be offset by 

decreasing the body’s total NIS inhibition load by 0.843 μmol/L SPEC. To achieve this, all of 

the exposure to perchlorate at the RfD (i.e., 0.014 μmol/L SPEC), all of the typical nitrate 

exposure (i.e., 0.167 μmol/L SPEC), and half of the typical thiocyanate exposure (i.e., 0.667 

μmol/L SPEC) would have to be eliminated to offset the decrease in %TIU from borderline mild 

iodide deficiency. Such a reduction in the total NIS inhibition load is not practical. All nitratecontaining foods would have to be eliminated from the diet, to include bacon, beef, sausage, 

potatoes, and carrots, and most of the foods rich in thiocyanate would have to be eliminated from 

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the diet, to include cabbage, broccoli, Brussels sprouts, corn (maize), cauliflower, cabbage, 

radishes, spinach, tomatoes, and milk. 

Furthermore, thiocyanate may have a regulatory function in normal physiology 

(Middlesworth 1986). Thiocyanate is continually synthesized in the normal rat. In the absence 

of all dietary intake of thiocyanate in the rat, the thiocyanate serum concentration actually 

increased, from 500 μg/dl to 800 μg/dl, during the fasting (Middlesworth 1986, figure 1). These 

data indicate that serum thiocyanate in rats is maintained in a normal range. This suggests that 

significantly reducing serum thiocyanate in humans from a normal range is not biologically 

achievable. 

In conclusion, reducing the average exposure to NIS inhibitors is not an effective solution 

to compensate for iodide deficiency. The only effective manner to address the adverse health 

effects of a low %TIU resulting from iodide deficiency is to increase the intake of iodide in the 

diet. 

9.3 Application of UFs in a Multifactorial Cumulative Risk Assessment 

The conventional approach of deriving an RfD in a single contaminant characterization is 

to apply one or more UFs to a LOAEL, NOAEL, or BMD, to address uncertainties in the data to 

ensure the RfD is below an exposure that might induce an adverse effect in a sensitive 

population. The NAS Committee applied a UF of 10 to the NOEL to derive the recommend 

perchlorate RfD of 0.0007 mg/kg-day. The number, type, and magnitude of UFs to apply in the 

derivation of an RfD is a matter of scientific judgment. This is a major source of contention in 

the derivation of a perchlorate RfD. The following table calculates the estimated total goitrogen 

load in an adult for various applications to UFs to the perchlorate NOEL of 0.007 mg/kg-day, 

which correspond to several DWELs (sample calculation not shown, but similar to previous 

calculations): 

Description of 

Dose Level 

Drinking Water 

Equivalent 

Level (DWEL) 

External Dose 

(mg/kg-day) 

Corresponding 

Uncertainty 

Factor (UF) 

Calculated Total 

Goitrogen Load 

(μmol/L SPEC) 

Greer NOEL 245 ppb 0.007 0 1.567 - ClO4 RfD 24.5 ppb 0.0007 10 1.511 

California 

Drinking Water Limit 6.0 ppb 0.00017† 40.8† 1.5034 

Massachusetts 

Drinking Water Limit 2.0 ppb 0.000057† 122.5† 1.5012 

EPA draft RfD 1.0 ppb 0.00003 233.3* 1.5006 

Provided to assess the 

impact of a large UF on 

the TIU 0.5 ppb 0.000014 500 1.5003 

* EPA’s draft perchlorate RfD was 0.00003 mg/kg-day external dose, but was derived from a different POD using a 

UF of 300. 

† For this evaluation of the impact of applying different UFs to the setting of a perchlorate RfD on the TIU, the 

external perchlorate dose and UF listed were back calculated from the Greer NOEL to arrive at the State’s Drinking 

Water Limits (this not the manner in which the States set their limits). 

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The following table summaries the calculated TIU, %TIU, and percentage increase in 

TIU in an adult at various applications to UFs to the perchlorate NOEL of 0.007 mg/kg-day, 

which corresponds to several DWELs (sample calculation not shown, but similar to previous 

calculations): 

Description of 

Dose Level 

Drinking Water 

Equivalent Level 

(DWEL) 

Calculated 

Total Iodide 

Uptake in an 

Adult 

(TIU) 

Percentage TIU 

of Baseline 

(%) 

Change in 

%TIU from 

Baseline 

Greer NOEL 245 ppb 0.35881x 100 baseline 0 

ClO4 

-

RfD 24.5 ppb 0.36617x 102.05 2.05 

California 

Drinking Water Limit 6.0 ppb 0.36718x 102.33 2.33 

Massachusetts 

Drinking Water Limit 2.0 ppb 0.36748x 102.42 2.42 

EPA draft RfD 1.0 ppb 0.36756x 102.44 2.44 

Provided to assess the impact 

of a large UF on the TIU 0.5 ppb 0.36761x 102.45 2.45 

Applying a UF of 10 to the NOEL reduces the perchlorate DWEL from 245 ppb to 24.5 

ppb, which would increase an adult’s TIU by 2.05%. Applying a UF of 40.8 to the NOEL 

reduces the perchlorate DWEL to 6.0 ppb; this further reduction in the perchlorate DWEL from 

24.5 ppb to 6.0 ppb increases an adult’s TIU by only 0.28%. Applying a UF of 122.5 to the 

NOEL reduces the perchlorate DWEL to 2.0 ppb; this further reduction in the perchlorate DWEL 

from 6.0 ppb to 2.0 ppb increases an adult’s TIU by only 0.09%. Applying a UF of 233.3 to the 

NOEL reduces the perchlorate DWEL to 1.0 ppb; this further reduction in the perchlorate DWEL 

from 2.0 ppb to 1.0 ppb increases an adult’s TIU by only 0.02%. Applying a UF of 500 to the 

NOEL reduces the perchlorate DWEL to 0.5 ppb; this further reduction in the perchlorate DWEL 

from 1.0 ppb to 0.5 ppb increases an adult’s TIU by only 0.01%. 

In short, this calculation shows that the use of an increasing UF value has the surprising 

result of having only a minimal impact on the TIU. This is contrary to the intent of the use of 

UFs in deriving an RfD. The explanation of this result is that a single chemical risk assessment 

is based on the assumption that the chemical is the principal cause (i.e., dominant stressor) of the 

adverse effect. So, if the exposure to the single chemical is kept sufficiently below the POD, the 

adverse effect will be avoided in even the most sensitive human subpopulation. However, 

perchlorate is only one of four stressors that affect the TIU of the NIS. Perchlorate also 

contributes the least amount of stress of the four NIS stressors and explains why the application 

of a UF to perchlorate exposure has a minimal effect on the TIU. Since the mechanism of 

toxicity results from the lack of a sufficient uptake of iodide to make an adequate supply of 

thyroid hormones for proper brain development during gestation and lactation, the concept of 

UFs should be applied to the TIU, which addresses the integrated result from the simultaneous 

exposure to all four stressors. The magnitude of the TIU is the single variable that determines a 

favorable or unfavorable outcome in this public health issue. In other words, since a low TIU 

leads to the adverse effect of brain damage, the minimum TIUs observed in the human 

population need to be kept above the TIU level that results in adverse effects. To apply UFs to 

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the TIU, the equivalent LOAEL or NOAEL TIU value must be determined; this will be 

discussed in the next section. 

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9.4 Determining %TIU Levels of Concern 

9.4.1 Identifying a %TIU(LOAEL) in Pregnant Women to Prevent Subtle Mental 

Deficits in Children 

The Tonacchera Model can be used to estimate the LOAEL %TIU in pregnant women 

when fetal brain damage occurs. The Tonacchera Model states: 

TIU || [I-

] / (1.22 + (SPEC)) 

where: the symbol || means “proportional to” 

If the SPEC is held constant (i.e., the level of NIS inhibitors remains the same), then, 

 TIU || [I-] 

Therefore, when the SPEC(Normal), then %TIU(LOAEL) is given by: 

%TIU(LOAEL) = ([I-

](Fetal brain damage) ÷ [I-] (Normal pregnant women) ) x 100% 

Since subtle fetal brain damage is known to occur in moderately iodide-deficient 

pregnant women (Bleichrodt 1989; Vermiglio 2004; Vermiglio 1990), as before, using UIC as a 

surrogate, the [I-

](Fetal brain damage) is 50 μg/L. The other information need is the recommended 

healthy UIC in pregnant women (i.e., [I-

] (Normal pregnant women)). Several credible sources have 

opined on the recommended UIC for pregnant women. Instead of relying on a single source, the 

average recommended UIC for pregnant women was determined and found to be 204 μg/L. The 

following table summarizes the sources and recommended UICs for pregnant women: 

Source 

Recommended Iodide 

Intake in Pregnant Women 

(μg/day) 

Recommended Urinary 

Iodide Concentration 

(μg/L) 

WHO/UNICEF/ICCIDD* 200 200-300 

Dr. Francois Delange, MD** 225-300 150-230 

WHO Technical Consultant Group*** 225-375 150-249 

Recommend Dietary Allowances (RDA)† 220† 150†† 

Average Value => 258 204 

* Source: Delange 2005, p 278, table 11E.8. 

** Source: Delange 2004. 

*** Source: ATA 2006. 

† Source: NAP 2000. 

†† Source: Pearce 2004. 

Therefore, the %TIU(LOAEL) in pregnant women is calculated as follows: 

%TIU(LOAEL) = ([I-](Fetal brain damage) ÷ [I-] (Normal pregnant women) ) x 100% 

%TIU(LOAEL) = (50 μg/L ÷ 204 μg/L) x 100% 

%TIU(LOAEL) = 24.5% 

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From the observed subtle brain damage in the offspring of moderately iodide-deficient 

pregnant women (Bleichrodt 1989; Vermiglio 2004; Vermiglio 1990), the LOAEL in pregnant 

women is estimated to be 24.5 %TIU. This agrees with 22.7%TIU(Hypothyoxinemia) observed to 

generate hypothyroxinemia in women exposed to excess amounts of thiocyanate (Banerjee 

1997b). Furthermore, inducing hypothyroxinemia in pregnant women is consistent with the 

proposed mechanism that an insufficient supply of maternal fT4 during gestation starves the 

developing fetal brain of an adequate supply of thyroid hormones, resulting in fetal brain 

damage. Also of note, 50% of the moderately iodide-deficient pregnant women in the Vermiglio 

2004 study were observed to have hypothyroxinemia. Eleven of the 16 children born to 

moderately iodide-deficient pregnant women in the Vermiglio 2004 study had ADHD. 

The 24.5 %TIU(LOAEL) integrates the combined effects of all four NIS stressors into a 

single variable. In a cumulative risk assessment, this is the numerical value that the concept of 

UFs shall be applied to. In a single chemical risk assessment, UFs are applied to the LOAEL or 

NOAEL to derive an RfD to address the uncertainties inherent in the data. If this concept is 

applied to the %TIU(LOAEL), typically a UF of 10 is applied to a LOAEL to estimate a NOAEL. 

And as in the case of the NAS Committee, an intraspecies UF of 10 was applied to derive the 

perchlorate RfD. Using this simplified template for the estimation of UFs to apply to the 

%TIU(LOAEL), a total UF of 100 would be used. The application of a UF of 100 to 24.5 

%TIU(LOAEL) (i.e., to back off the adverse effect level by two orders of magnitude) would derive 

a %TIU(RfD equivalent) = 2450%. This value corresponds to a UIC of about 5000 μg/L. This is 

biologically unrealistic. Obviously, the conventional rules of applying UFs during a single 

chemical risk assessment do not apply to this cumulative risk assessment. 

9.4.2 Identifying a %TIU(NOAEL) in Pregnant Women to Prevent Subtle Mental 

Deficits in Children 

The cumulative risk assessment of this public health issue recognizes that the doseresponse curve for iodide exposure to the thyroid is a u-shape curve (Delange 2005, p 281). 

When the UIC of pregnant women is below 50 μg/L, adverse effects are observed in their 

children, but when the UIC of pregnant women goes above 500 μg/L (ATA 2006), other adverse 

clinical effects can occur. By analogy, since %TIU represents the same mechanism (i.e., the 

amount of iodide available to the thyroid), the %TIU dose-response curve will also be u-shaped. 

A UIC of 50 μg/L and 500 μg/L result in a %TIU in a pregnant woman of 24.5 %TIU(LOAEL) and 

245 %TIU(Excess limit), respectively. 

EPA’s Integrated Risk Information System defines a NOAEL as: 

The highest exposure level at which there are no biologically significant increases 

in the frequency or severity of adverse effect between the exposed population and 

its appropriate control; some effects may be produced at this level, but they are 

not considered adverse or precursors of adverse effects (IRIS 2007). 

The traditional use of a NOAEL in a single chemical exposure is as the lowest chemical 

exposure level without adverse effects. The typical use of a NOAEL assumes that increasing 

chemical exposure produces an increasing the severity or frequency of adverse effects. 

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However, the %TIU dose-response curve is u-shaped. An adverse effect occurs when the %TIU 

is either too high or too low. Therefore, the application of the NOAEL concept to a u-shape 

dose-response curve generates the need for two NOEALs to prevent insufficient uptake of iodide 

and to prevent an excessive uptake of iodide. For the purposes of identifying each NOAEL, the 

following labels will be used: %TIU(NOAEL) and %TIU(NOAEL for excess). A UIC above 500 μg/L in 

pregnant women (ATA 2006) is excessive and results in a %TIU(NOAEL for excess) of 245%. 

The key is to define a %TIU(NOAEL) that is “ . . . [the lowest %TIU] exposure level at 

which there are no biologically significant increases in the frequency or severity of adverse effect 

between the exposed population and its appropriate control.” A %TIU(Insufficient NOAEL) can be 

derived from the following adverse effects occurring in children of mildly iodide-deficient 

pregnant women: 

•	 Mildly iodide-deficient pregnant women have children with statistically significant 

delayed reaction times to visual stimuli (Lombardi 1995; Vitti 1992). Although not a 

particularly severe adverse effect, delayed reaction times to visual stimuli is a sensitive 

test for a subtle change that is reproducible between studies and is undesirable. 

•	 The heterogeneous thyroid performance within the human population (i.e., the 5th item to 

be addressed by this cumulative risk assessment) can be observed in the children of 

mildly iodide-deficient pregnant women. Newborns of mildly iodide-deficient women 

have an increased frequency of 0 to 16.9% of elevated TSH above the < 3% background 

levels observed in iodide-sufficient areas. In other words, at least 83% of the newborns 

are unaffected by mild iodide deficiency, while up to 16.9% are potentially adversely 

affected. Although a mildly iodide-deficient pregnant woman is able to adapt to mild 

iodide deficiency and will probably remain euthyroid throughout pregnancy, the fetus’s 

thyroid is less able to adapt to iodide deficiency. Fetal hypothyroxinemia is induced by 

iodide deficiency because the immature fetal thyroid is unable to increase its avidity for 

iodide despite up-regulation of NIS expression in the fetal thyroid and placenta during 

iodide deficiency (Delange 2005a). The increased iodide clearance rate will further 

decrease the iodine stores of the fetal thyroid and decrease fetal T4 synthesis (Delange 

2005a). Tracer studies in mild hypothyroid neonatal rats (i.e., elevated TSH without 

below normal fT4) have observed increased D2 deiodinase activity of the central nervous 

system (CNS) in order to compensate for a decreased supply of T3 in the CNS. This 

implies that newborns with elevated TSH (analogous to mild hypothyroidism in the 

neonatal rats) may have had to activate their D2 deiodinase compensatory mechanism in 

the CNS (Bianco 2005, p 123). This indicates that the fetal thyroid may not be making 

enough T4 during mild iodide deficiency and increases the possibility that subtle brain 

damage may have occurred. However, epidemiology studies have neither identified nor 

evaluated this subgroup (i.e., elevated TSH newborns) for the possibility of subtle mental 

deficits. Neonatal TSH is the single indicator that focuses on potential brain damage, 

which is the major impact of iodide deficiency (Delange 1998). An additional adverse 

effect in neonates with elevated TSH is observed in a study by Calacirua, in which infants 

with elevated TSH at neonatal screening are at risk for developing subclinical 

hypothyroidism in early childhood (odds ratio 44.6%; 95% CI 38.8-50.4%) (Calaciura 

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2002). Delange also points out that neonates with elevated TSH levels are at a high risk 

of developing subclinical hypothyroidism in infancy and early childhood (Delange 1998). 

Clearly, the observed delayed reaction time, the increased occurrence of elevated TSH in 

newborns, and the increased risk of developing subclinical hypothyroidism meet the NOAEL 

definitional requirement that the NOAEL exposure level must be above the level of “increases in 

the frequency or severity of adverse effect(s).” Since mild iodide deficiency in pregnant women 

is characterized by a UIC between 100 μg/L to 50 μg/L, using a UIC of 100 μg/L prevents a 

%TIU exposure level that induces an increased frequency of elevated TSH levels in the iodidesensitive subpopulation. Therefore, the %TIU(NOAEL) in pregnant women is calculated as 

follows: 

%TIU(NOAEL) = ([I-](inc. freq. of elevated TSH in newborns) ÷ [I-] (Normal pregnant women) ) x 100% 

%TIU(NOAEL) = (100 μg/L ÷ 204 μg/L) x 100% 

%TIU(NOAEL) = 49% 

9.4.3 Identifying a %TIU(RfD) in Pregnant Women to Prevent Subtle Mental Deficits 

in Children 

EPA’s Framework for Cumulative Risk Assessment (EPA 2003) defines an (RfD) as, “An 

estimate (with uncertainty spanning 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 non-cancer effects during a lifetime (EPA 2003).” 

EPA’s risk assessment guidance states that a reduction of the intraspecies UF from a 

default of 10 is to be considered only if the POD is determined from the data obtained from the 

susceptible subpopulation (EPA 2002, p 4-43). Since the POD (i.e., %TIU(NOAEL) = 49%) was 

determined in the susceptible subpopulation, an intraspecies UF of 1 should be used. However, 

the %TIU(NOAEL) should not be used as the %TIU(RfD), because the uptake of iodide is not the 

only step in the production and use of thyroid hormones in the body that is disrupted by chemical 

exposures. Numerous inorganic and synthetic chemicals have been documented to interfere with 

almost every major step in the production, transport, and peripheral tissue metabolism of thyroid 

hormones (Howdeshell 2002, p 344, table 1). The following table provides examples of 

chemicals that interfere with several major thyroid hormone steps: 

Thyroid Hormone Step Examples of Chemicals that Interfere 

Iodide uptake by the NIS 2,4-D, Aldrin, Lead, PBBs, 

Iodide oxidation by thyroid peroxidase Lindane, Malathion, Mancozeb 

Circulatory transport in blood 

(e.g., binding to transthyretin) 

Dioxtylphthalate, DDT metabolites, 

Dichloroprop, Difocol, Lindane, Malathion, 

Cellular metabolism of T4 to T3 by Type I or Type II 5’­

deiodinase in peripheral tissues Cadmium, Lead, PCB, Dixoin 

Increase cellular elimination by glucuronidation of T4/T3 by 

the stimulation of the glucuronidase enzyme Acetochlor, DDT, PBBs, PCBs, Dioxin 

Source: Howdeshell 2002 (for full list - see p 344, table 1). 

As stated in the EPA’s Framework for Cumulative Risk Assessment, an aspect of a 

cumulative risk assessment is that it can be qualitative as well as quantitative (EPA 2003). This 

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aspect is necessary to incorporate risk from other chemical exposures in which there is 

insufficient information to accurately quantify the amount of risk, although the presence and 

nature of the risk is known. The rational for using a nonquantitative approach for setting the 

%TIU(RfD) is also based on the understanding of the mechanism of action for thyroid hormones 

(Yen 2005). Proper fetal/neonate brain development occurs when a sufficient supply of 

intracellular T3 binds to the thyroid hormone receptor TRβ-1. The T3/TRβ-1 is a ligandregluated transcription factor that along with other transcriptional cofactors causes the expression 

of genes containing thyroid hormone response elements in the promoter region (Yen 2005). 

In short, thyroid hormones represent a “chemical signal” in the body that regulates the 

transcription of genes during CNS development. Although the %TIU(NOAEL) provides enough 

uptake of iodide by the thyroid to make a sufficient supply of T4, subsequent loses of T4 in 

subsequent thyroid hormone steps due to the potential interference by other industrial chemicals 

(e.g., higher than normal cadmium exposure during gestation) could result in a insufficient suppy 

of T4 at the target brain tissue. In other words, the “chemical signal” started out strong enough at 

the thyroid, but was weakened by interference from other industrial chemicals along the way that 

resulted in an insufficient “chemical signal” in the developing brain cell. The amount of 

interference by these other industrial chemicals is qualitatively known to occur, but is not easily 

quantified for use in a conventional risk assessment. However, a cumulative risk assessment 

allows this interference effect to be qualitatively factored into the assessment. The concept is 

that if the original “chemical signal” is made strong enough, it may tolerate some interference 

along the way and still be strong enough at the end to be correctly interrupted and allow for the 

appropriate level of gene transcription to occur for proper brain development. 

The qualitative factor proposed is the equivalent of using a 1.5 UF. Therefore, the 

%TIU(RfD) in pregnant women is calculated as follows: 

%TIU(RfD) = %TIU(NOAEL) x 1.5 UF 

%TIU(RfD) = 49% x 1.5 UF 

%TIU(RfD) = 74% 

At a typical 1.501 μmol/L SPEC level, a %TIU of 74% corresponds to a UIC in pregnant 

women of 151 μg/L. Since the median UIC in pregnant women in the NHANES III survey was 140 

μg/L, this means about half of U.S. pregnancies each year occur below the %TIU(RfD). This indicates a 

clear need to increase the %TIU levels in this half of the U.S. pregnant women population with these 

low %TIUs. 

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9.5 Calculating the %TIU in Pregnant Women at Various Perchlorate Exposures 

The Clewell perchlorate PBPK model identifies that the internal perchlorate exposure 

(i.e., internal indices) is not the same for each life stage for the same external perchlorate dose 

(Clewell 2007, p 423, table 4). Specifically, the conversion factor from an external to internal 

perchlorate dose is 2.5 times higher at 0.001 mg/kg-day for a pregnant woman than for an adult. 

In other words, a pregnant woman experiences 2.5 times more NIS inhibition from higher serum 

perchlorate level than an adult for the same external perchlorate dose of 0.001 mg/kg-day. 

Therefore, the calculated TIUs in pregnant women will be slightly lower then the calculated 

TIUs in adults (see previous table in Section 9.1.4) at the same external perchlorate dose. The 

following table summaries the calculated TIUs for pregnant women with various external 

perchlorate exposures levels (sample calculation not shown, but similar to previous calculations): 

External ClO4 

-

Dose 

(mg/kg-day) 

Internal 

ClO4 

-

Dose in 

Pregnant 

Women 

(μmol/L) 

Serum 

Perchlorate 

Equivalent 

Conc. (SPEC) 

in Pregnant 

Women 

(μmol/L) 

Iodide 

Nutritional 

Level in 

Pregnant 

Women 

(Fraction of 

Normal) 

Calculated 

Total 

Iodide 

Uptake 

(TIU) 

%TIU Calculated 

from the 

Tonacchera 

Model 

0.000066* 

(in 

nonpregnant 

adults) 0.0013* 1.501† 1.00 0.3675x 

100 

(nonpregnant 

adult %TIU 

reference level) 

0.000066* 0.00325 1.503 1.00 0.3672x 99.9 

0.000175 

(1⁄4 RfD) 0.0088 1.510 1.00 0.3663x 99.7 

0.0007 

(RfD) 0.035 1.536 1.00 0.3628x 98.7 

0.007 (NOEL) 0.399** 1.900 1.00 0.3205x 87.2 

0.000066* 0.00325 1.503 0.49*** 0.1799x 49.0 

0.000175 

(1⁄4 RfD) 0.0088 1.510 0.49*** 0.1795x 48.8 

0.0007 

(RfD) 0.035 1.536 0.49*** 0.1778x 48.4 

0.007 (NOEL) 0.399** 1.900 0.49*** 0.1570x 42.7 

* Median perchlorate exposure in U.S. population (Blount 2006a). 

† From median NIS inhibitor exposures in the U.S. population (calculated in Section 7.2.1).
 

** Used an estimated conversion factor of 0.0425 mg/L per .0075 mg/kg-day using a linear interpolation from the 

Clewell perchlorate PBPK model. 

*** Average recommended urinary iodide concentration in pregnant women = 204 μg/L (see Section 9.4.1). 

Therefore, an iodide nutritional level of 0.49 in pregnant women corresponds to 100 μg/L, which is the urinary iodide 

limit for mild iodide deficiency. 

In a pregnant woman at the average recommended iodide nutrition level, the Tonacchera 

Model calculates a 98.7 %TIU at the perchlorate RfD of 0.0007 mg/kg-day, which corresponds 

to a 24.5 ppb DWEL. By comparison, the calculated %TIU in adults at the perchlorate RfD is 

99.6% (see table in Section 9.1.4). Therefore, the Tonacchera Model estimates that a pregnant 

woman’s %TIU is affected more by the same external perchlorate exposure than is an adult’s 

%TIU (i.e., a decrease of 0.9 %TIU). In a pregnant woman, the Tonacchera Model also 

calculates a 99.7 %TIU at a perchlorate exposure level of 0.0000175 mg/kg-day (i.e., a quarter of 

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the perchlorate RfD level), which corresponds to a 6.1 ppb DWEL. Therefore, in a pregnant 

woman, the Tonacchera Model estimates a 1.0% increase in the %TIU when the perchlorate 

drinking water exposure is lowered from 24.5 ppb to 6.1 ppb. 

By contrast, in a pregnant woman with mild iodide deficiency (i.e., with a UIC of 100 

μg/L) , the Tonacchera Model calculates a 48.4 %TIU at the perchlorate RfD of 0.0007 mg/kgday, which corresponds to a 24.5 ppb DWEL. This is a decrease of 50.3%TIU as compared to a 

pregnant woman at the average recommended iodide nutrition level having a same perchlorate 

exposure at the perchlorate RfD (i.e., 98.7% minus 48.4%). In other words, for a pregnant 

woman with perchlorate exposure at the RfD, decreasing her iodide intake from the average 

recommended iodide nutrition level (i.e., a UIC of 204 μg/L) to a mildly iodide-deficient level 

(i.e., a UIC of 100 μg/l) lowers her TIU level by 50.3%TIU. By comparison, a pregnant woman 

with mild iodide deficiency and a perchlorate exposure level of 0.0000175 mg/kg-day (i.e., a 

quarter of the perchlorate RfD), which corresponds to a 6.1 ppb in drinking water, would have a 

calculated %TIU of 48.8%. Therefore, in a pregnant woman with mild iodide deficiency, the 

Tonacchera Model estimates only a 0.4 % increase in the %TIU when the perchlorate drinking 

water exposure is lowered from 24.5 ppb to 6.1 ppb. Clearly, an increase of 0.4% in %TIU in 

mildly iodide-deficient pregnant women estimated from the potential act of lowering the 

perchlorate drinking water exposure from 24.5 ppb to 6.1 ppb is not sufficient to offset the 

50.3% decrease in %TIU from the loss of iodide in the diet during mild iodide deficiency during 

pregnancy. This example in mildly iodide-deficient pregnant women shows that the lack of 

iodide is the dominant stressor affecting this public health issue and the risk to the public from a 

low %TIU during pregnancy and lactation cannot be managed without addressing iodide 

deficiency within this sensitive subpopulation. 

Evaluating these results from another perspective, the Greer study observed a %TIU of 

98.2% ± 8.3% at the perchlorate NOEL of 0.007 mg/kg-day. Therefore, the predicted 1.0% 

reduction in the TIU in pregnant women when the DWEL is lowered from 24.5 ppb to 6.1 ppb is 

not statistically detectable in a human experiment. From the Greer data, a 1.0% change in the 

%TIU is only 1/12th the random variation observed in the %TIU at the perchlorate NOEL. By 

contrast, the Greer study measures a %TIU range of 45% to 155% in the population before the 

exposure to perchlorate (i.e., in the 37 test subjects at the BV). Therefore, %TIU varied ± 55% 

in Greer’s study population without measuring any thyroid hormones outside the normal ranges 

for TSH, fT4, tT4, or tT3. Potentially regulating perchlorate at a DWEL of 6.0 ppb instead of 

24.5 ppb prevents about a 1% change in TIU in pregnant women; a 1%TIU change is only a 

small fraction of the ± 55% normal variation observed in the %TIU at baseline in the Greer study 

population. Therefore, decreasing the perchlorate drinking water concentration from 24.5 ppb to 

6.0 ppb will not have a significant effect on the %TIU observed in people. A single chemical 

risk assessment of perchlorate only characterizes a small portion of this public health issue and 

does not explain the factors that cause the TIU to vary ± 55% in the Greer study population. 

Furthermore, managing only the exposure to perchlorate and not managing the other NIS 

stressors will have little effect of ensuring the %TIU is above the NOAEL for pregnant women. 

This cumulative risk assessment estimates the %TIU(NOAEL) = 49% for pregnant women. Only 

by managing the exposure to all four NIS stressors can the %TIU be held above the %TIU(NOAEL) 

for pregnant women. 

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Using a cumulative risk assessment approach to characterize this public health issue, the 

large variation in the %TIU observed in the Greer study can be easily explained. The NIS 

stressor that can account for such a large variation in the %TIU observed in the Greer study 

population is the dominant NIS stressor – iodide. If all the variation in %TIU was from the 

variation in iodide nutrition alone, the Greer study population would be expected to have a UIC 

in the range of 65 μg/L and 225 μg/L. This agrees with iodide variation observed in the NHANE 

III survey, which identified the 10th to the 90th percentile UIC in the U.S. population to be 45 

μg/L to 386 μg/L. 

A 1.0% reduction in %TIU could be offset by a 1.0% increase in the UIC in pregnant 

women. At a borderline iodide-deficient UIC of 100 μg/L in pregnant women, a 1.0% increase 

in %TIU is caused by the additional intake of about 1.1 μg of iodide. The American Thyroid 

Association (ATA) recommends that pregnant and lactating women take a daily prenatal 

vitamin/mineral supplement containing 150 μg of iodide (ATA 2006). Taking an iodidecontaining prenatal vitamin/mineral supplement would easily offset a 1% reduction in %TIU. 

Furthermore, since iodized salt in the United States contains about 100 ppm potassium iodide or 

77 μg iodide/gram of salt (Dunn 1998), the increased consumption of 14.3 mg of iodized salt 

would provide the 1.1 μg of iodide required to offset the 1% reduction in %TIU. Since a pinch 

of table salt weighs about 460 mg, 14.3 mg of salt is equivalent to about 1/32nd of a pinch of 

salt. Since a smidgen of table salt weighs about 230 mg, 14.3 mg of salt is equivalent to about 

1/16th a smidgen of salt. 

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10. Approaches to Address this Public Health Issue 

10.1 %TIU Exposure Levels of Concern 

Any effective remedy must ensure that pregnant and nursing women have a sufficient 

TIU to prevent subtle mental deficits in their children. The cumulative risk assessment 

determined that a %TIU(insufficient RfD) of 74% in pregnant and nursing women is the exposure 

level at which the risk begins for this public health issue. As the %TIU decreases below 74%, 

the level of risk increases. The risk levels of concern are characterized as follows: 

•	 If the combination of exposures to the four NIS stressors induces a %TIU less than 74% 

(i.e., the %TIU(Insufficient RfD) level), the possibility for mental deficits exists. At a typical 

total NIS inhibition load, a %TIU corresponds to a UIC of 151 μg/L in pregnant women. 

•	 If the combination of exposures to the four NIS stressors induces a %TIU less than 49% 

(i.e., the %TIU(NOAEL) level), the fetus and nursing infant are under thyroid stress (and the 

thyroid-sensitive subpopulations are at greater risk) and the potential for mental deficits 

increases. At a typical total NIS inhibition load, a %TIU corresponds to a UIC of 100 

μg/L in pregnant women. 

•	 If the combination of exposures to the four NIS stressors induces a %TIU less than 24.5% 

(i.e., the %TIU(LOAEL) level), mental deficits occur in a percentage of the offspring 

population. The lower the %TIU, the frequency and severity of the mental deficits 

increases. At a typical total NIS inhibition load, a %TIU corresponds to a UIC of 50 

μg/L in pregnant women. 

10.2 Remedy Approach 

The public health issue of potential subtle mental deficits in children is initiated by an 

insufficient amount of iodide being taken up by the thyroid in pregnant women, fetuses, and 

nursing infants. An excess exposure to any one (or more) of the four NIS stressors (i.e., lack of 

iodide, thiocyanate, nitrate, and perchlorate) can result in a TIU less than 74%TIU in pregnant 

women. Unfortunately, the current federal and State remedy being considered or implemented to 

address this public health issue is the exposure to only one of the four NIS stressors. The federal 

and State governments are considering or have implemented a maximum contaminant limit 

(MCL) for perchlorate, which will limit the perchlorate exposure from drinking water. 

Using a cumulative risk assessment approach, everyone in the U.S. population has a 

continual exposure to all four NIS stressors. An excess exposure to any one (or more) of the four 

NIS stressors can result in a TIU less than 74 %TIU in pregnant women. To address the risk, the 

exposure levels to all four NIS stressor have to be considered and potentially managed. To 

manage the risk, the proposed goal should be to ensure that the 90th percentile of pregnant 

women have a %TIU greater than %TIU(RfD) of 74%. Currently, the exposure to NIS stressors 

results in about half of all pregnant women having a %TIU less then the %TIU(RfD). 

Furthermore, the proposed goal should be to ensure that >99th percentile of pregnant women 

have a %TIU greater than the %TIU(NOAEL) of 49%. Currently, the exposure to NIS stressors 

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results in about 29% of all U.S. pregnant women having a %TIU less then the %TIU(NOAEL) 

value. Most troubling, the current exposure to NIS stressors results in up to 7% of all U.S. 

pregnant women having a %TIU less then the %TIU(LOAEL) of 24.5%. 

10.2.1 Exposure Management of Each NIS Stressor 

An adequate amount of iodide uptake in pregnant women, fetuses, and nursing infants is 

addressed by preventing an excess exposure to any one (or more) of the four NIS stressors. The 

cumulative risk assessment identified that the relative influence of each of the NIS stressors on 

this public health issue can be described as follows: 

Lack of iodide > SCN- >> NO3

- >> ClO4­

Where: “ > ” means “greater than” 

 “ >> ” means “much greater than” 

Therefore, the management of the lack of iodide stressor has the largest effect on the 

%TIUs value observed in pregnant women, followed by the management of thiocyanate 

exposure. By contrast, the management of nitrate and perchlorate will have the least effect on 

the %TIUs observed in pregnant women. However, the exposure management to all four NIS 

stressors is required to ensure pregnant women have a healthy %TIU level, which is greater than 

74%. 

10.2.1.1 Lack of Iodide Stressor 

The cumulative risk assessment has identified that the lack of iodide NIS stressor is the 

dominant stressor in this public health issue. Unfortunately, the iodide exposure assessment in 

the sensitive group indicates that 6.9% of pregnant women are moderately iodide deficient and 

an additional 22% are mildly iodide deficient. The iodide exposure assessment indicates that up 

to 29% of the U.S. population of pregnant women is at a higher risk for mental deficits in their 

children. Obviously, the amount of iodide in the diet of a significant portion of the U.S. pregnant 

women population is dangerously low. Therefore, correcting poor iodide nutrition among 

pregnant and lactating women is needed to ensure the healthy brain development of the fetus and 

nursing infant. 

This is where using a cumulative risk assessment approach to this public health issue is 

critical. A cumulative risk assessment allows stressors that are outside EPA’s legislative 

mandates, authority, or expertise to be identified and addressed in cooperation with other federal 

agencies (EPA 2003, xviii), health organizations, and technical disciplines. EPA authority 

extends to the regulation of environmental contaminates. However, according to the Tonacchera 

Model, the dominant stressor in this public health issue is the iodide nutrition level (i.e., the lack 

of iodide in the diet) in pregnant and lactating women. Overseeing and correcting the iodide 

nutrition level is clearly not in EPA’s legislative mandate; however, addressing the iodide 

deficiency in U.S. pregnant women is essential to effectively addressing this public health issue. 

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The NAS Committee was fundamentally aware of the crucial role of iodide nutrition 

during pregnancy. The NAS Committee wrote in the summary of their report that “[The NAS 

Committee] . . . recommends that consideration be given to adding iodide to all prenatal 

vitamins” (NAS 2005, p 18). The NAS Committee also wrote that same statement as the last 

line in its report (NAS 2005, p 196). The issue of whether prenatal vitamins should contain 150 

μg of iodide falls into the legislative authority the National Institutes of Health, the FDA (see 

further discussion below), and the charter of the Institute of Medicine (IOM). The NAS 

Committee’s recommendation for adding iodide to all prenatal vitamins should or could be 

addressed through the Federal Government’s Perchlorate Interagency WorkGroup. However, 

this NAS recommendation has not been acted upon within that environmental arena. 

10.2.1.1.1 Iodide Supplementation During Pregnancy and Lactation 

The NAS Committee, ATA, and leading thyroid experts have recommended iodide 

supplementation during pregnancy and lactation. The NAS Committee recommends that 

consideration be given to adding iodide to all prenatal vitamins (NAS 2005, p 18, 196). ATA 

recommends that pregnant and lactating women take a daily prenatal vitamin/mineral 

supplement containing 150 μg of iodide (ATA 2006). Zimmerman and Delange have 

encouraged both the European Thyroid Association and the European Office of ICCIDD to 

recommend that supplement manufacturers include 150 μg/day iodide in prenatal supplements 

(Zimmermann 2004). Mild to moderate iodide deficiency during pregnancy adversely affects 

thyroid function of the mother and newborn and mental development of the offspring; these 

adverse effects can be prevented or minimized by iodide supplementation (Zimmermann 2004). 

Unfortunately, not all prenatal vitamin supplements contain the recommended 150 μg 

iodide, and the use of iodide-containing prenatal vitamins is unacceptably low. The IOM 

currently does not recommend including iodide in prenatal vitamins (Sullivan 2007). Therefore, 

many prenatal vitamins do not contain iodide (Sullivan 2007). Only 1 of the 19 vitamins (i.e., 

5%) listed for prenatal use in the 2006 Physician’s Desk Reference contained 150 μg of iodide, 

while the other 18 vitamins listed contained no iodide (ATA 2006). Pearce identifies an abstract 

that reports 44 of 69 (i.e., 64%) prenatal vitamins marketed in the United States contain some 

level of iodide (Pearce 2007a). In the Boston study of 57 lactating women, only 41 (72%) took a 

multivitamin, but only 3 lactating women (7%) took multivitamins containing iodide (Pearce 

2007). The Boston study concludes that “47% of women sampled may have been providing 

breast milk with insufficient iodine to meet infants’ requirements” (Pearce 2007). Furthermore, 

younger women of lower education and of certain ethnic groups tend not to use supplements on a 

regular basis (Sullivan 2007). 

The 234 pregnant women taking no iodide supplement in the NHANES III survey had a 

median UIC of 141 μg/L (ATA 2006). By contrast, the 100 pregnant women taking a daily 150 

μg iodide supplement in the NHANES III survey had a median urinary concentration of 169 

μg/L (ATA 2006). The fraction of women excreting excessive amounts of iodide (i.e., > 500 

μg/L) was not appreciably higher than those not taking a daily iodide supplement. ATA 

concludes that taking a 150 μg iodide supplement per day during pregnancy “appears to be safe” 

(ATA 2006). Benefits of correcting iodide deficiency outweigh the risks (Delange 2005, p 283). 

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The risk from iodide intake is U-shaped, meaning that there is a risk from too little or too 

much iodide. Our analysis identified that an iodide supplement of about 150 μg of iodide per 

day will reduce the risk from a low TIU during pregnancy and nursing. This is consistent with 

Glinoer’s recommendation for the use of a prenatal vitamin pill containing 100-200 μg of iodide 

per day (Glinoer 2005, p 1092). However, the responsibility of assessing the need for and 

implementing prenatal vitamin use belongs to the medical community. 

10.2.1.1.2 Participation of the Medical Community 

A cumulative risk assessment allows stressors that are outside EPA’s legislative 

mandates, authority, or expertise to still be addressed by involving the expertise of other federal 

agencies (EPA 2003, page xviii), health organizations, and technical disciplines. The medical 

community has the authority to determine whether iodide-containing prenatal vitamins should be 

recommended to address this public health issue. Our analysis identifies that taking iodidecontaining prenatal vitamin will reduce the risk from a low TIU during pregnancy and nursing. 

Furthermore, our analysis identifies that iodide-containing prenatal vitamins should be taken at 

least 3 months before pregnancy, during pregnancy, and during nursing. 

In regard to the concern that pregnant women with a UIC above 150 μg/L taking a 

prenatal vitamin containing iodide might develop health problems from excess iodide, the 234 

pregnant women taking no iodide supplement in the NHANES III survey had a median UIC of 

141 μg/L (ATA 2006). By contrast, the 100 pregnant women taking a daily 150 μg iodide 

supplement in the NHANES III survey had a median UIC of 169 μg/L (ATA 2006). The 

fraction of women excreting excessive amounts of iodide (i.e., > 500 μg/L) was not appreciably 

higher than those not taking a daily iodide supplement. ATA concludes that taking a 150 μg 

iodide supplement per day during pregnancy “appears to be safe” (ATA 2006). In general, the 

benefits of correcting iodide deficiency outweigh the risks (Delange 2005, p 283). 

An approach to avoiding this potential for excess iodide exposure during pregnancy is to 

simply measure the UIC during prenatal care. If the UIC is below 150 μg/L, the use of an 

iodide-containing prenatal vitamin is warranted. If the UIC is above 150 μg/L, the use of an 

iodide supplement may not be necessary, and the potential risk of inducing excess iodide intake 

is eliminated. On a related concern, if the pregnant woman’s UIC is below 50 μg/L (i.e., 

indicating moderate iodide deficiency), the medical community may need to consider more 

aggressive intervention, such as iodide supplementation and levothyroxine (Glinoer 1995), to 

avoid or minimize the severity of subtle mental deficits in her child. 

The most appropriate preventative and therapeutic approach to avoiding excessive stress 

on the pregnant mother’s thyroid from the inadequate uptake of iodide is to systematically 

increase the iodide supply as early as possible during gestation and continuing through lactation 

if the mother intends to breast feed (Glinoer 2005, p 1092). This can be easily achieved by the 

use of a multivitamin pill containing 100-200 μg of iodide per day (Glinoer 2005, p 1092). 

However, if an individual has been iodide deficient (i.e., mild or moderate) for a long time before 

pregnancy, a lag period of about one trimester (i.e., 3 months) is inevitable before the thyroid 

function normalizes following the onset of iodide supplementation (Glinoer 2005). This is the 

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reason for recommending taking iodide containing prenatal vitamins 3 months prior to 

pregnancy, if possible. 

The effectiveness of iodide supplementation during pregnancy can be observed in the six 

randomized, controlled trials of iodide supplementation involving a total of 450 pregnant women 

with mild to moderate iodide deficiency (Zimmermann 2004, Table 2). In all six trials, iodide 

supplementation resulted in a significant increase in maternal UIC. The six trials found no 

increase in maternal thyroid autoimmunity or in the prevalence or severity of postpartum thyroid 

dysfunction. Iodide supplementation is efficacious for both the mother and newborn. Iodide 

supplementation is associated with significantly reduced maternal thyroid volume and generally 

lowers maternal TSH levels. Iodide supplementation prevents or minimizes the enlargement of 

newborn thyroid volume and increased Tg levels. However, there are no clinical studies on the 

effect iodide supplementation has on long-term outcomes, such as a child’s mental development. 

Results of Treatment of Mild Iodide Deficiency during Pregnancy with Iodide 

Supplementation 

 The benefits of iodide supplementation can be observed in a 1995 prospective doubleblind, randomized trail study of 180 euthyroid women with excess thyroid stimulation who were 

divided into three equal groups (Glinoer 1995). Excess thyroid stimulation was determined by 

meeting the following criteria: serum Tg > 20 μg/L and (fT4 index < 1.23 or T3/T4 ratio > 25 

x10-3). The screening of 2,000 pregnant women resulted in 180 pregnant women (i.e., 9% of the 

screened population) meeting the excess thyroid stimulation criteria. Only pregnant women at 

less than 16 weeks of gestation were enrolled in the study. Treatment began from the day of 

enrollment to delivery. (Note: iodide supplementation in this study did not start 3 months before 

pregnancy or at conception). Sixty women received a daily placebo (no treatment); another 60 

women received a daily 100 μg iodide supplement, and 60 women received a daily dose of 131 

μg iodide supplement and a daily dose of 100 μg levothyroxine. 

The results from the1995 prospective double-blind, randomized trail study show the 

benefits of supplementing pregnant women with iodide: 

•	 Mean serum Tg in newborns of mothers with iodide supplementation was significantly 

lower versus the controls (65 ± 6 μg/L vs 113 ± 9 μg/L (p = 0.0001), respectively). 

•	 The mean UIC in newborns of mothers with iodide supplementation was significantly 

higher versus controls (77 ± 8 μg/L vs 43 ± 4 μg/L (p = 0.0001), respectively). Even 

with the improvement of 100 μg iodide/day supplementation, the mean neonate UIC of 

77 μg/L falls still short of the WHO-recommended mean neonate UIC of 150 μg/L 

(Delange 2005). Furthermore, optimal neonate UIC is reported be as high as 180-225 

μg/L (Delange 2004). Since the study used only a 100 μg dose of iodide/day 

supplementation, the NAS Committee’s and ATA’s recommendation for prenatal 

vitamins to contain 150 μg iodide is supported by these data. 

•	 The mean thyroid volume in newborns of mothers with iodide supplementation was 

significantly less versus controls (0.76 ± 0.05μg/L vs 1.05 ± 0.05 μg/L (p = 0.0001), 

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respectively). In other words, the mean thyroid volume in newborns without maternal 

iodide supplementation was 40% larger than newborns with maternal iodide 

supplementation. Furthermore, glandular hyperplasia was already present at birth in 10% 

of the neonates without maternal iodide supplementation (Glinoer 2005, p 1092). By 

contrast, no instance of neonatal goiter is observed in neonates born to mothers with 

iodide supplementation (Glinoer 2005, p 1092). 

•	 Mothers with iodide supplementation have significantly higher iodide levels in their 

breast milk versus controls (61 ± 10 μg/L vs 29 ± 2 μg/L (p = 0.001), respectively). 

Breast milk less than 50 μg/L is considered by WHO/UNICEF/ICCIDD to indicate 

iodide deficiency in the population (Delange 1994 p,109). Clearly, iodide 

supplementation dramatically improves the iodide levels in breast milk, which directly 

improves the iodide nutrition of nursing infants in which critical brain development is 

occurring. 

These observations indicate that iodide supplementation during pregnancy reduces the 

stress on the fetal thyroid so that the risk for developing subtle mental deficits is minimized. 

10.2.1.2 Thiocyanate Stressor 

The cumulative risk assessment has identified that the thiocyanate NIS stressor at typical 

exposure concentrations is a medium-impact stressor in this public health issue. Common, 

healthy vegetables in the diet are a significant and natural source of thiocyanates (Tonacchera 

2004). Foods particularly rich in thiocyanate include cabbage, cauliflower, broccoli, Brussels 

sprouts, corn (maize), mustard seed, and milk. For example, a nonsmoking individual consumed 

100 grams of raw Brussels sprouts each day for a week to document a rise in thiocyanate serum 

levels from 31 to 80 μmol/L. Furthermore, dietary thiocyanate exposure exhibits a seasonal 

change of about 10 μmol/L presumably due to seasonal changes in the composition of the diet 

(Foss 1986). Therefore, the human body is continuously and unavoidable exposed to 

thiocyanate. 

Thiocyanate may have a regulatory function in normal physiology (Middlesworth 1986). 

Thiocyanate is continually synthesized in the normal rat. In the absence of all dietary intake of 

thiocyanate in the rat, the thiocyanate serum concentration actually increased from 500 μg/dl to 

800 μg/dl during the fasting (Middlesworth 1986, Figure 1). These data indicate that serum 

thiocyanate in rats is maintained in a normal range. A “kidney threshold” is reported to exist in 

humans at a thiocyanate serum threshold of 200-300 μmol/L (Tonnacchera 2004). These data 

imply that humans also synthesize and maintain thiocyanate serum concentrations in a normal 

range. Therefore, any remedy to significantly lower thiocyanate exposures – to decrease serum 

thiocyanate concentration, which will increase the %TIU in adult and in particular pregnant 

women – is not practical and will not be effective, due to the maintenance of thiocyanate serum 

concentrations by the body. 

The human nonsmoker thiocyanate exposure is typically in the range of 10-70 μmol/L in 

the serum, and most occurs naturally through the consumption of healthy vegetables. Except for 

the potential for occupational exposures to cyanide (e.g., electroplaters), the amount of 

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uncontrolled environmental cyanide exposure in the U.S. population is negligible (i.e., cyanide is 

metabolized by the body into thiocyanate). By contrast, the major source of excess thiocyanate 

exposure in humans occurs through smoking. The act of smoking increases the mean 

thiocyanate serum concentration by a factor of 2.5x (i.e., from 40 to 100 μmol/L). The 

thiocyanate exposure in smokers is typically in the range of 80-120 μmol/L. The increased risk 

of fetal brain damage from smoking while pregnant is yet another reason to encourage pregnant 

women not to smoke. Encouraging individuals not to smoke is clearly an activity outside EPA’s 

legislative mandate and authority. 

In reviewing the potential for cyanide exposure in the U.S. population, the U.S. drinking 

water limit (i.e., MCL) for cyanide is 0.2 mg/L (De Groef 2006). The consumption of 2 liters 

water at the cyanide MCL per day would result in an exposure of 0.4 mg cyanide/day. This 

amount of cyanide would be metabolized into 894 μg thiocyanate/day (i.e., assuming 100% 

conversion). Using the OPEC equation to convert exposure to 894 μg thiocyanate/day into 

perchlorate equivalent amount results in 51 μg OPEC (i.e., the perchlorate RfD = 49 μg/day). 

Therefore, consumption of 2 liters of drinking water contaminated at the MCL for cyanide 

induces the same amount of NIS inhibition as perchlorate exposure at the RfD. 

10.2.1.3 Nitrate Stressor 

The cumulative risk assessment has identified that the nitrate NIS stressor at typical 

exposure concentrations is a weak impact stressor in this public health issue. Human exposure to 

nitrate is both exogenous and endogenous. Exogenous human nitrate exposure is from diet 

through the consumption of primarily vegetables. Nitrate is common in food (Tonacchera, 2004) 

and occurs in green leafy vegetables. Nitrate is also added to processed meats as a preservative. 

Nitrate commonly contaminates both surface water and groundwater sources of drinking water. 

Furthermore, the endogenous human nitrate exposure is from the body’s production of nitric 

oxide, which is subsequently converted into nitrate by various types of cells in the body (NAS 

1995, page 37). Therefore, humans are continuously and unavoidably exposed to nitrate. 

Most nitrogenous materials in natural waters tend to be converted to nitrate, so all sources 

of combined nitrogen, particularly organic nitrogen and ammonia, should be considered as 

potential nitrate sources (EPA 2008). Primary sources of organic nitrates include human sewage 

and livestock manure, especially from feedlots. The primary inorganic nitrates which may 

contaminate drinking water are potassium nitrate and ammonium nitrate, both of which are 

widely used as fertilizers (EPA 2008). According to the Toxics Release Inventory, releases to 

water and land totaled over 112 million pounds from 1991 through 1993. The largest releases of 

inorganic nitrates occurred in Georgia and California at 12.0 and 21.8 million pounds (EPA 

2008). EPA’s 1999 study on the occurrence of contaminants in Public Water Systems (PWSs) 

regulated under the Safe Drinking Water Act identified that of the 8,988 groundwater PWSs 

tested for nitrate, 85.9% had at least one analytical result above the minimum reporting limit, 

11.4% had at least one analytical result above 1⁄2 MCL, and 2.3% had at least one analytical 

result above the MCL (EPA 1999, Appendix A). 

 In studies from Denmark and the United Kingdom, the average nitrate intake is 

estimated to be about 40-50 mg/day for adults (Tonacchera 2004). This value is on the low end 

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of the nitrate intake estimates reported by the National Academy of Sciences (see Section 3.4 

above; NAS 1995, p 35-43) and represents a bias low estimate of the average daily nitrate intake. 

In the Western world, the typical nitrate serum concentration ranges from 10-140 μmol/L with 

the mean nitrate serum concentration being between 30-50 μmol/L (Tonacchera 2004). The 

Tonacchera Model indicates that at typical nitrate exposure level of 40 μmol/L, nitrate 

contributes only about 11% of the body’s typical total NIS inhibition load of 1.501 μmol/L. 

Potentially reducing the nitrate exposure will only marginally improve the %TIU values in 

humans and in particular pregnant women. 

The U.S. drinking water MCL for nitrate is 10 mg of nitrate nitrogen per liter4 (EPA 

1991b), which is equivalent to 44 mg of nitrate per liter (NAS 1989, p 5, 11, 45). The 

conversion factor between these two analytical units is 1 mg of nitrate nitrogen per liter, equal to 

4.429 mg of nitrate per liter. Therefore, the consumption of 2 liters water at the EPA nitrate 

MCL per day would result in an exposure of 88 mg nitrate/day (i.e., this is about twice the 

average daily intake of nitrate). Using the OPEC equation to convert exposure to 88 mg 

nitrate/day into PEC results in a 587 μg/day OPEC (i.e., the perchlorate RfD = 49 μg/day). 

Therefore, consumption of 2 liters of drinking water contaminated at the nitrate MCL induces 12 

times the amount of NIS inhibition as perchlorate exposure at the RfD (De Groef 2006). 

In 1999, EPA identified that 2.3% of the groundwater PWSs tested for nitrate had at least 

one analytical result above MCL (EPA 1999, appendix A). Furthermore, in 1999, EPA 

identified that 11.4% of groundwater PWSs tested for nitrate had at least one analytical result 

above 1⁄2 MCL (EPA 1999, appendix A). The consumption of 2 liters of drinking water 

contaminated at the 1⁄2 nitrate MCL induces 6 times the amount of NIS inhibition as perchlorate 

exposure at the RfD. In regard to private groundwater wells, 9% of domestic groundwater wells 

(irrespective of depth to groundwater) sampled by the U.S. Geological Survey’s National WaterQuality Assessment Program during 1993-2000 had nitrate levels above the EPA nitrate MCL of 

44 mg/L for drinking water (Nolan 2002). This nitrate contamination of private groundwater 

wells is a potential health issue for the estimated 42 million Americans that drink unregulated 

groundwater from their own private wells. By comparison, the consumption of drinking water 

contaminated with 3.7 mg/L of nitrate (i.e., 1/12th the nitrate MCL) has the equivalent NIS 

inhibition as the consumption of drinking water contaminated at 24.5 ppb perchlorate. 

Considering the nitrate contamination of both PWSs and private wells, about 10% of U.S. 

population is consuming nitrate-contaminated water at levels that induce at least 6 times more 

NIS inhibition than perchlorate exposure at the RfD. Therefore, lowering the public’s nitrate 

exposure provides a more meaningful opportunity to lower the public’s NIS inhibition load (i.e., 

a more meaningful opportunity to lower public risk) than to lower the public’s perchlorate 

exposure below the perchlorate RfD. 

4

 The current EPA MCL for nitrate is drinking water is expressed as 10 mg nitrate nitrogen per liter (i.e., which is 

the mass of nitrogen present in the nitrate form per liter), which is equivalent to 44 mg of nitrate per liter (NAS 

1989, 5, 11, 45). The conversion factor between these two analytical units is 1 mg of nitrate nitrogen per liter = 

4.429 mg of nitrate per liter (NAS 1989, 10). 

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10.2.1.4 Perchlorate Stressor 

The cumulative risk assessment has identified that the thiocyanate NIS stressor at the 

RfD exposure concentrations is a very weak impact stressor in this public health issue. The 

FDA’s perchlorate TDS identified that perchlorate is present at very low levels in food, primarily 

through the consumption of dairy and vegetables (Murray 2008, p 5). Furthermore, both 

surface and ground sources of drinking water can be contaminated with perchlorate. Therefore, 

the human body is continuously and unavoidably exposed to low levels of perchlorate. 

The FDA TDS estimates a perchlorate intake of 5.4 to 6.8 μg/day from food in 25- to 30- 

year-old women (Murray 2008, table 5). The FDA TDS estimate of perchlorate intake agrees 

with the CDC biomonitoring data that estimates the median perchlorate exposure in the U.S. 

population is 4.6 μg/day (Blount 2006). The Tonacchera Model indicates that a median 

perchlorate exposure level of 4.6 μg/day, observed in the CDC biomonitoring data, contributes 

only about 0.09% of an adult body’s typical total NIS inhibition load of 1.501 μmol/L. 

Furthermore, the Tonacchera Model indicates that a perchlorate exposure at the RfD contributes 

only 0.9% (less than 1%) of an adult body’s typical total NIS inhibition load of 1.501 μmol/L. 

Finally, the Tonacchera Model also estimated a 0.3% increase in %TIU in adults and 1.0% 

increase in the %TIU of pregnant women if the actual perchlorate drinking water exposure is 

reduced from 24.5 ppb to 6.1 ppb. Therefore, potentially reducing the maximum perchlorate 

exposure in drinking water from 24.5 ppb to 6.0 ppb or lower will not significantly improve the 

%TIU values in adults and, in particular, pregnant women. 

The remedy of potentially decreasing the perchlorate DWEL from 24.5 ppb to 6.1 ppb 

will help only a very small portion of the at-risk population. Conceptually, a theorectial 1.0% 

increase in %TIU applied to the entire at-risk poplution would be expected to increase at most 

2% of the pregnant woman population above of critical %TIU level of 49% (i.e., %TIU(NOAEL) ), 

which would leave about 27% of the pregnant woman population below the critical %TIU level. 

However, the potential remedy of lowering the perchlorate DWEL from 24.5 ppb to 6.0 ppb will 

increase the %TIU in only a small subset of this population. The EPA’s Unregulated 

Contaminant Monitoring Rule (UCMR 1) data indicate only 2.13% of the PWSs are 

contaminated with perchlorate greater than 7 μg/L, which effects a population size of 

approximately 2.2 million people (EPA 2007, table 5). Therefore, about 0.7% of the U.S. 

population (i.e., 2.2 million ÷ 300 million x 100%) is potentially exposed to drinking water 

containing > 7 ug/L and potentially able to benefit from the lowering of perchlorate exposure in 

drinking water. Assuming pregnant women are evenly distributed throughout the U.S. 

population, the act of lowering the perchlorate DWEL from 24.5 ppb to 6.0 ppb would be 

expected to increase at most 0.014% of the annual pregnant woman population (i.e., 2% x 0.007) 

above of critical %TIU level of 49%. This potential remedy leaves 28.99% of the estimated 29% 

of U.S. pregnant woman population with a %TIU < 49% still at risk for subtle mental deficits in 

their children. In other words, the act of lowering perchlorate drinking water exposure below 

24.5 ppp provides a neglible decrease in the size of the at-risk population. By contrast, 

implementing prenatal vitamins containing iodide has the potential to pull all 29% of the iodidedeficient pregnant women in the United States successfully above the critical %TIU(NOAEL) value, 

and at a relatively low implementation cost. 

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A 1.0% reduction in %TIU could be offset by a 1.0% increase in the UIC in pregnant 

women. At a borderline iodide-deficient UIC of 100 μg/L in pregnant women, a 1.0% increase 

in %TIU is caused by the additional intake of about 1.1 μg of iodide. ATA recommends that 

pregnant and lactating women take a daily prenatal vitamin/mineral supplement containing 150 

μg of iodide (ATA 2006). Taking an iodide-containing prenatal vitamin/mineral supplement 

would easily offset a 1% reduction in %TIU. Furthermore, iodized salt in the United States 

contains about 100 ppm potassium iodide or 77 μg iodide/gram of salt (Dunn 1998). The 

increased consumption of 14.3 mg of iodized salt would provide the 1.1 μg of iodide required to 

offset the 1% reduction in %TIU. Since a pinch of table salt weights about 460 mg, 14.3 mg of 

salt is equivalent to about 1/32nd of a pinch of salt. Since a smidgen of table salt weights about 

230 mg, 14.3 mg of salt is equivalent to about 1/16th a smidgen of salt. 

In reviewing the exposure to NIS inhibitors in drinking water, about 11.4% of 

groundwater PWSs tested for nitrate had at least one analytical result above 1⁄2 MCL, which 

corresponds to an amount of NIS inhibition 6 times greater than the amount of NIS inhibition 

from perchlorate exposure at the DWEL (i.e., at the RfD). Furthermore, about 2.3% of 

groundwater PWSs tested for nitrate had at least one analytical result above MCL, which 

corresponds to an amount of NIS inhibition 12 times greater than the amount of NIS inhibition 

from perchlorate exposure at the RfD. Furthermore, these data indicate that a significant portion 

of the U.S. population has a much higher risk from NIS inhibition from nitrate from drinking 

water than the risk from NIS inhibition from perchlorate exposure from drinking water at the 

RfD. 

From a risk management standpoint, the Federal Government and the States should 

weigh the effectiveness of potential remedies to this public health issue and the cost of 

implementing each remedy against the health benefits to be derived by each remedy. The 

following are three potential remedies that can potentially address this public health issue; each 

has varying degrees of effectiveness: 

•	 Add iodide to prenatal vitamin supplements and implement their use before and during 

pregnancy and lactation. 

•	 Reassess the nitrate drinking water MCL and consider lowering the MCL to decrease the 

public’s NIS inhibition exposure. 

•	 Lower the perchlorate drinking water exposure level from 24.5 ppb to 6 ppb or lower. 

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11. Conclusion 

The OIG Analysis of the scientific literature identified that the risk from perchlorate 

exposure is only part of the larger public health issue that is defined by the subtle mental deficits 

occurring in children born to mothers with low maternal TIU during pregnancy and nursing. The 

TIU results from the combined biological effect of four NIS stressors acting on the thyroid: 

thiocyanate, nitrate, perchlorate, and lack of iodide. Diet constantly exposes everyone to each of 

the four NIS stressors, and an individual’s TIU level is the result of the combined effect of all 

four NIS stressors, not just perchlorate exposure. The OIG Analysis concludes that a single 

chemical risk assessment of perchlorate is not sufficient to assess and characterize the combined 

human health risk from all four NIS stressors. However, both EPA’s draft perchlorate RfD from 

the Argus rat study and the NAS Committee’s recommended perchlorate RfD from the Greer 

study used a single chemical risk assessment approach. By contrast, our cumulative risk 

assessment better characterizes the nature and sources of risk affecting this public health issue. 

All four NIS stressors meet EPA’s risk assessment guidance requirements for conducting 

a cumulative risk assessment using the dose-addition method. In the OIG Analysis, we 

conducted a cumulative risk assessment and determined that the risk from each of the four NIS 

stressors is not equal. The OIG Analysis also independently confirmed that EPA’s perchlorate 

RfD is conservative and protects human health, but limiting perchlorate exposure does not 

effectively address this public health issue. Potentially lowering the perchlorate drinking water 

limit from 24.5 ppb to 6 ppb does not provide a meaningful opportunity to lower the public’s 

risk. By contrast, addressing moderate and mild iodide deficiency that occurs in about 29% of 

the U.S. pregnant and nursing population appears to be a more effective approach of increasing 

TIU to healthy levels during pregnancy and nursing, thereby reducing the frequency and severity 

of permanent mental deficits in children. 

The NAS Committee recommended that “. . . consideration be given to adding iodide to 

all prenatal vitamins” (NAS 2005, p 18). Our independent cumulative risk assessment came to a 

similar conclusion. The most effective and efficient approach for reducing the health risk of 

permanent mental deficits in children from low maternal TIU during pregnancy and nursing is to 

require that iodide be added to all prenatal vitamins and to encourage women to take them before 

and during pregnancy and while nursing. 

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Appendix A 

“Whole Mixture” Approach to the 

Cumulative Risk Assessment of Perchlorate 

An alternative approach to conducting a cumulative risk assessment is the “whole 

mixture” approach. Risk assessors can accomplish a whole mixture approach by developing a 

statistical model on human epidemiological data. An example of this whole mixture approach 

that has received a lot of attention is the Blount analysis (Blount 2006, Table 6) and the 

subsequent Steinmaus analysis of the NHANES 2001-2002 epidemiological study. The Blount 

analysis and the Steinmaus analysis represent statistical models fitted to the NHANES 2001­

2002 epidemiological data. The Blount analysis predicted a decrease of 1.64 μg/dL in tT4 serum 

from a 13 μg/day perchlorate exposure in women ≥ 12 yrs of age with a UIC ≤ 100 μg/L due to 

the NIS inhibition of perchlorate. These women are moderate to mildly iodide deficient. The 

subsequent Steinmaus analysis (Steinmaus 2007) on the same NHANES 2001-2002 

epidemiological data concluded that increasing thiocyanate exposure potentiates the rate of 

decrease in tT4 with increasing perchlorate exposure. 

Using EPA criteria, our review indicates that the whole mixture approach to risk 

assessment of perchlorate (i.e., Blount analysis and the Steinmaus analysis) is not sufficiently 

developed and corroborated to be either the basis for developing a perchlorate RfD or the basis 

for establishing a potential perchlorate drinking water limit for the following reasons: 

1.	 Section 3.1.3 of EPA’s Draft Guidance on the Development, Evaluation, and Application 

of Regulatory Environmental Models (November 2003) establishes the need to 

corroborate all environmental models before risk assessors use the models as the basis for 

rulemaking or regulation (EPA 2003a). The Blount and Steinmaus analyses represent a 

statistical model of the toxicity of perchlorate; their findings must be corroborated with 

other epidemiological data and other human exposure studies of perchlorate before they 

should be used as the basis for rulemaking. No human epidemiological study has 

corroborated the results of the Blount and Steinmaus analyses. To the contrary, the 

available epidemiological data of perchlorate-exposed pregnant women with UIC ≤ 100 

μg/L contradict the findings of the Blount and Steinmaus analyses. These 

epidemiological studies included the following: 

a.	 A cohort of 789 pregnant women (i.e., 396 from Cardiff, Wales; 311 from Turin, 

Italy; and 82 from Dublin, Ireland) with perchlorate exposure levels shows no 

association between urinary perchlorate levels and free T4 levels in the pregnant 

women as a group or in the subgroup of pregnant women with UIC ≤ 100 μg/L 

(Pearce 2007b). 

b.	 A cohort of 230 pregnant women (i.e., 128 from Los Angeles, California; 102 from 

Córdoba, Argentina) with low perchlorate exposure levels predicted by the Blount 

analysis to induce a reduction of tT4 shows no association between urinary 

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perchlorate levels and free T4 levels in the pregnant women as a group or in the 

subgroup of pregnant women with UIC ≤ 100 μg/L (Pearce 2008). 

c.	 From the 2005 Tellez cohort study (Tellez 2005) in three Chilean cities, a reanalysis 

of the data identified 16 of the pregnant women had UIC ≤ 100 μg/L (Gibbs 2008). 

The reanalysis shows no association between urinary perchlorate levels and free T4 

levels in this subset of pregnant women with UIC ≤ 100 μg/L. 

2.	 Pregnant women with a tT4 decrease of 3.2 μg/dL from a normal tT4 level have 

hypothyroidism. Researchers have observed that the children of these women have lower 

cognitive, attention, and motor performance scores (Haddow 1999, tables 2 and 4). 

However, we have identified adverse effects in children of pregnant women under less 

thyroid stress than hypothyroidism (i.e., hypothyroxinemia and low TIU). Therefore, the 

Blount analysis, which predicted a decrease of 1.64 μg/dL in tT4 from a 13 μg/day 

perchlorate exposure in women with a UIC ≤ 100 μg/L, is anticipated by our technical 

review by ICF International to be sufficient to induce adverse effect in the children. 

Thus, from the Blount analysis, 13 μg of perchlorate exposure per day could be 

considered the LOAEL. However, the NAS Committee derived its recommended 

perchlorate RfD from a NOEL of 0.007 μg/kg-day. Assuming a 70-kg person and a 

LOAEL of no less than 10 times greater than the NOEL, the estimated LOAEL 

equivalent from the Greer study would be at least roughly 4,900 μg/day. The Blount 

analysis suggests that the perchlorate toxicity is significantly more toxic (i.e., more than 

300 times more toxic) than what the NAS Committee and all previous perchlorate studies 

have indicated. Typical human exposures to the other common NIS inhibitors – 

thiocyanate and nitrate – induce substantially more NIS inhibition than 13 μg/day of 

perchlorate, but are not observed to induce thyroid hormone changes in the Blount 

analysis. Therefore, the increased toxicity of perchlorate reported in the Blount analysis 

would not be accounted for by the known mechanism of perchlorate toxicity: the 

inhibition of NIS. Furthermore, the Blount analysis does not propose a new mechanism 

of perchlorate toxicity that accounts for their reported increased toxicity of perchlorate. 

Until researchers can explain the increased toxicity of perchlorate by a verified biological 

mechanism, regulators should not use the Blount analysis as a basis for developing a 

perchlorate RfD, nor should it be used as the basis for establishing a drinking water limit. 

3.	 The NHANES 2001-2002 epidemiological urinary data are from a single, untimed spot 

urinalysis and can vary due to dilution or concentration of the urine (i.e., due to an 

individual’s hydration status). A common technique to eliminate this variation in the spot 

urinalysis is to normalize the iodide urine concentration against creatinine, resulting in 

the analysis expressing iodide excretion as μg of iodide/g of creatinine (i.e., μg/g 

creatinine) instead of μg of iodide/L of urine. Lamm has successfully repeated Blount’s 

statistical analysis of the NHANES 2001-2002 epidemiological data only when his 

analysis measures UIC as μg/L (Lamm 2007). However, when Lamm repeats the 

statistical analysis using only women of childbearing age (ages 15-44) and UIC measured 

as μg/g creatinine, the statistical significance of the relationship between decreasing tT4 

with increasing perchlorate exposure in women with low UIC is lost. The statistical 

significance of this relationship should be present regardless of whether the analysis 

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expresses UIC in μg/L or μg/g of creatinine. This inconsistency suggests that the 

relationship between tT4 and perchlorate reported in the Blount analysis might be an 

artifact in the NHANES dataset. 

4.	 Section 3.2 of EPA’s Supplementary Guidance for Conducting Health Risk Assessment of 

Chemical Mixtures establishes a major requirement for the use of a whole mixture risk 

assessment approach – the composition of the mixture must be stable over time; the 

relative proportions of chemicals in the mixture are roughly constant so that the mixture 

can be treated as though it were a single chemical (EPA 2000). Examples of EPA whole 

mixture risk assessments include Araclor 1016, Araclor 1254, and coke oven emissions. 

However, human exposure to each of the four NIS stressors varies independently based 

on the dietary intake preferences of the individual. Therefore, the mixture of the four 

NIS stressors is not a fixed, stable composition. Thus, a whole mixture approach is not 

well suited to assessing the toxicity for this public health issue since exposure to each of 

the four NIS stressors varies. 

5.	 The OIG Analysis indicates that the toxicity of perchlorate is not fixed and cannot be 

described by a single RfD; rather, the toxicity of perchlorate changes in response to the 

exposure level of the other three NIS stressors, especially the lack of iodide stressor. 

From clinical observations of populations with endemic cretinism and from the OIG 

Analysis, at higher iodide nutrition levels, the body can tolerate a higher total goitrogen 

load. The converse is also true: at lower iodide nutrition levels, the body’s tolerance of 

total NIS inhibition is much less. The Blount analysis also observes this trend in the 

toxicity of perchlorate. The Blount analysis reports that 13 μg/day of perchlorate 

exposure induces toxicity (i.e., a decrease in tT4) in women with UICs ≤ 100 μg/L, but 

the same 13 μg/day of perchlorate exposure is nontoxic in women with UICs ≥ 100 μg/L. 

From both clinical observations (i.e., in Africa and India) and our cumulative risk 

assessment, reducing NIS inhibition exposure cannot correct a low TIU caused by iodide 

deficiency. Only the addition of iodide to the diet can correct a low TIU caused by iodide 

deficiency. 

6.	 Section 3.1.3.2 of EPA’s Draft Guidance on the Development, Evaluation, and 

Application of Regulatory Environmental Models defines robustness as the capacity of a 

model to perform equally well across the full range of environmental conditions (EPA 

2003a). This guidance further elaborates that if the data used to calibrate the model are 

identical or statistically similar to the dataset used to corroborate a model, the study did 

not provide an independent measure of the model’s performance. Therefore, the 

Steinmaus analysis does not corroborate the Blount analysis, because both studies use the 

same NHANES 2001-2002 dataset. Furthermore, CDC plans to use the next NHANES 

dataset to continue to examine this interface of environmental perchlorate exposure, 

iodine levels, and tobacco smoke exposure (thiocyanate). However, repeating the 

analysis in the next NHANES dataset would not represent an independent evaluation of 

the robustness or the performance of the model because it is still a statistically similar 

dataset. 

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7.	 The December 13, 2006, ATA Public Health Statement commented on the Blount 

analysis. ATA identified that the NHANES 2001-2002 measured serum thyroxine as tT4 

rather than as free T4. Free T4 is the most frequently used clinical measurement and the 

physiologically available form of thyroxine. 

8.	 The scientific literature reports that several dietary NIS stressors biologically affect the 

uptake of iodide, not to mention other chemical exposures affecting other subsequent 

biological steps in the production of T4 that could contribute to the decrease in serum tT4 

observed in the Blount analysis. The Blount analysis reports an R2

 value of 0.240. R2 is 

a statistical value called the “proportion of variation explained,” and is the proportion of 

scatter in a dataset that the statistical model explains. The R2

 value of 0.240 reported in 

the Blount analysis shows that perchlorate accounts for only 3% of the variation seen in 

the serum tT4 (Charnley 2008). If only 3% of the tT4 change predicted by the Blount 

analysis was from perchlorate, the toxicity level of perchlorate reported in the Blount 

analysis would be more consistent with the other perchlorate studies and with the NASrecommended perchlorate RfD. 

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ADHD 

ATA 

BMC 

BMD 

BMDL 

BV 

CDC 

CG 

CH 

CHO 

CI 

ClO4

­

CNF 

CNS 

d 

DWEL 

EAR 

EPA 

FDA 

fT3 

fT4 

GAO 

HA 

HRL 

HNA 

I

­

I2 

ICCIDD 

IDA 

IOM 

IQ 

IRIS 

ISA 

LNA 

LOAEL 

MCL 

mg 

mg/day 

mg/kg-day 

mg/L 

mU/l 

NAP 

Appendix C 

List of Acronyms and Abbreviations 

attention-deficit/hyperactivity disorder 

American Thyroid Association 

benchmark concentration 

benchmark dose 

benchmark dose lower confidence limit 

baseline visit 

Centers for Disease Control and Prevention 

cyanogenic glycosides 

congenital hypothyroidism 

Chinese hamster ovary 

confidence interval 

perchlorate 

Chilean nitrate fertilizer 

central nervous system 

Cohen’s d-value 

drinking water equivalent level 

estimated average requirement 

U.S. Environmental Protection Agency 

Food and Drμg Administration 

free triiodothyronine 

free thyroxine 

Government Accountability Office 

health advisory 

health reference level 

high-nitrate area 

iodide 

iodine 

International Council for the Control of Iodine Deficiency Disorders 

iodide-deficient area 

Institute of Medicine 

intelligence quotient 

Integrated Risk Information System 

iodide-sufficient area 

low-nitrate area 

lowest-observed-adverse-effect-level 

maximum contaminant limit 

milligram 

milligram per day 

milligram per kilogram per day 

milligram per liter 

milli-international-units per liter 

National Academies Press 

C-1
 
 

 

 

 

 

 

10-P-0101 

NAS National Academy of Sciences 

NCEH National Center for Environmental Health 

NHANES National Health and Nutrition Examination Survey 

NIS sodium iodide symporter 

nmol/L nanomole per liter 

NO3

- nitrate 

NOAEL no-observed-adverse-effect-level 

NOEL no-observed-effect-level 

NPDWR National Primary Drinking Water Regulation 

NRC National Research Council 

OCEPA Office of Communications, Education, and Public Affairs 

OIG Office of Inspector General 

OPEC oral perchlorate equivalent concentration 

p probability 

PBPK physiologically based pharmacokinetic 

PEC perchlorate equivalent concentration 

pg/dL picogram per deciliter 

PII plasma inorganic iodide 

POD point of departure 

ppb part per billion 

ppm part per million 

RAIU radioactive iodide uptake 

RDA recommended dietary allowance 

RfD reference dose 

RPF relative potency factor 

RSC relative cource contribution 

SAB Science Advisory Board 

SCN- thiocyanate 

SD standard deviation 

SE standard error of the mean 

SPEC serum perchlorate equivalent concentration 

T3 triiodothyronine 

T4 thyroxine 

TDS Total Dietary Study 

Tg thyroglobulin 

TIU total iodide uptake 

%TIU percent total iodide uptake 

TSH thyroid-stimulating hormone (a.k.a. thyrotropin) 

tT3 total triiodothyronine 

tT4 total thyroxine 

UCMR Unregulated Contaminant Monitoring Rule 

UF uncertainty factor 

UIC urinary iodide concentration 

UNICEF United Nations International Children's Emergency Fund 

μg microgram 

μg/day mircrogram per day 

C-2
 
10-P-0101 

μg/dL microgram per deciliter 

μg/kg-day microgram per kilogram per day 

μg/L microgram per liter 

μmol/L micromole per liter 

μU/ml micro-international-units per milliliter 

USDA U. S. Department of Agriculture 

WHO World Health Organization 

WISC Wechsler Intelligence Scale for Children 

C-3
 
10-P-0101 

Appendix D 

Scientific Comments Received on the 

OIG Scientific Analysis of Perchlorate 

(External Review Draft) 

For this appendix, go to the following: 

www.epa.gov/oig/reports/2010/20100419-10-P-0101_appD.pdf 
10-P-0101 

Appendix E 

OIG Response to Comments on 

OIG Scientific Analysis of Perchlorate 

(External Review Draft) 

For this appendix, go to the following: 

www.epa.gov/oig/reports/2010/20100419-10-P-0101_appE.pdf 
10-P-0101 

Appendix F 

Distribution 

Office of the Administrator 

Assistant Administrator for Research and Development 

Assistant Administrator for Water 

Director, Office of Children’s Health Protection and Environmental Education 

Agency Follow-up Official (the CFO) 

Agency Follow-up Coordinator 

General Counsel 

Associate Administrator for Congressional and Intragovernmental Relations 

Associate Administrator for Public Affairs 

Audit Follow-up Coordinator, Office of the Administrator 

Audit Follow-up Coordinator, Office of Research and Development 

Audit Follow-up Coordinator, Office of Water 

Acting Inspector General