Occupational Carcinogens:

ELF MFs

Siemiatycki et al. (2004) published a list of

occupational carcinogens based largely on the

evaluations published by the International

Agency for Research on Cancer (IARC), augmented with additional information on the

extent of workplace exposure. They considered 28 agents as definite human occupational carcinogens (IARC group 1), 27 agents

as probable occupational carcinogens (group

2A), and 113 agents as possible occupational

carcinogens (group 2B). However, missing

from their list of occupational carcinogens is

magnetic fields (MFs) at extremely low frequencies (ELF; 3–3000-Hz), which were

classified as group 2B by IARC (2002).

IARC’s final conclusion (IARC 2002) is

as follows: 

Overall, extremely low frequency magnetic fields

were evaluated as possibly carcinogenic to

humans (IIB), based on the statistical association

of higher level residential ELF magnetic fields

and increased risk for childhood leukaemia.

Thus, although the evaluation is based on

epidemiologic studies of childhood leukemia,

the classification applies to all human exposure to ELF MFs, and thus also to occupational exposure. This interpretation has

been discussed and confirmed with an

IARC representative on their ELF MF

panel (Cardis E, personal communication).

Because enough workers are exposed to

ELF MFs to clearly meet the criteria for

occupational exposures set by Siemiatycki

et al. (2004), we are surprised that they did

not include it in their list of possible occupational carcinogens.

Other groups and agencies have applied

IARC’s criteria to the evaluation of ELF MF

carcinogenicity. The National Institute of

Environmental Health Sciences working

group (NIEHS 1998) evaluated the research

in that era and classified ELF EMFs (electric

and magnetic fields) as possibly carcinogenic

(group 2B); this classification was based on

the occurrence of chronic lymphocytic

leukemia (CLL) associated with occupational exposure. The California Department

of Health Services also evaluated the cancer

risks of EMF in 2002, and their reviewers

classified it as at least group 2B, including

childhood leukemia and adult brain cancer

(Neutra et al. 2002). 

Since the IARC evaluation, several relevant studies have been published—both

in vitro and in vivo work, as well as epidemiologic studies, including the following

examples. Tynes et al. (2003) reported an

association between exposure to calculated

residential MFs and cutaneous malignant

melanoma. In a cohort including all female

workers, Weiderpass et al. (2003) found an

association between exposure to electromagnetic fields and stomach and pancreatic

cancer; Villeneuve et al. (2002) found that

occupational MF exposure increased the

risk of glioblastoma multiforme; Håkansson

et al. (2002) investigated cancer incidence

in resistance welding workers exposed to

high levels of MF and found that men in

the very high exposure group showed an

increased incidence of tumors of the kidney, pituitary gland, biliary passages, and

liver; an exposure–response relationship was

indicated for these cancer sites. Women in

the very high exposure group showed an

increased incidence of astrocytoma I–IV,

with a clear exposure–response pattern. 

Ivancsits et al. (2002, 2003a, 2003b)

have shown that human lymphocytes

exposed to ELF MFs can generate DNA

single and double strand breaks from a flux

density as low as 35 μT and with a strong

correlation between both the intensity and

duration of the MF exposure. 

The IARC evaluation (IARC 2002)

ruled out a probable carcinogen classification

(group 2A) because the expert panel found

the animal studies were “inadequate evidence

of carcinogenicity.” This judgment was due

to many conflicting results in the repetition

of long-term animal experiments. In particular, Löscher and Mevissen (1995) reported

that MF exposure to Sprague-Dawley (SD)

rats after 7,12-dimethylbenz[a]anthracene

(DMBA) initiation increased breast tumors

in the exposed animals at 50 μT compared

with the control group (see also ThunBattersby et al. 1999). However, in a similar

study Anderson et al. (1999) found no evidence for a cocarcinogenic or tumor-promoting effect of MF exposure, but the study

used different substrains of SD rats than used

in the original study. Anderson et al. (2000)

stated that “the U.S. rats were more susceptible to DMBA than the European rats”; diet

and DMBA were from different sources, and

there were differences in environmental conditions and in MF exposure metrics.

Fedrowitz et al. (2004) compared two substrains of SD outbred rats; MF exposure significantly increased mammary tumor

development and growth in one of the

strains of rats but not in the other. These

data suggest that genetic background may

play a pivotal role in effects of MF exposure;

this which might explain the difficulties in

replicating the original animal studies of

breast tumor promotion. 

According to the criteria used by

Siemiatycki et al. (2004), a complete list

of occupational agents classified as possible human carcinogens would include

ELF MFs.

The authors declare they have no competing

financial interests.

Kjell Hanson Mild

National Institute for Working Life

Umeå, Sweden

Mats-Olof Mattsso

Lennart Hardell

Örebro University

Örebro, Sweden

Joseph D. Bowman

National Institute for Occupational 

Safety and Health

Cincinnati, Ohio

E-mail: jdb0@cdc.gov 

Michael Kundi

Medical University of Vienna

Vienna, Austria

K.H.M. was a member of IARC’s 2001

group of experts. M.O.M. and J.D.B. were

members of the NIEHS working group.

REFERENCES

Anderson LE, Boorman GA, Morris JE, Sasser LB, Mann PC,

Grumbein SL, et al. 1999. Effect of 13 week magnetic field

exposures on DMBA-initiated mammary gland carcinomas in female Sprague-Dawley rats. Carcinogenesis

20(8):1615–1620.

Anderson LE, Morris JE, Sasser LB, Löscher W. 2000. Effects

of 50- or 60-hertz, 100 μT magnetic field exposure in the

DMBA mammary cancer model in Sprague-Dawley rats:

possible explanations for different results from two laboratories. Environ Health Perspect 108:797–802.

Fedrowitz M, Kamino K, Löscher W. 2004. Significant differences in the effects of magnetic field exposure on

7,12-dimethylbenz(a)anthracene-induced mammary carcinogenesis in two substrains of Sprague-Dawley rats.

Cancer Res 64(1):243–251.

Håkansson N, Floderus B, Gustavsson P, Johansen C, Olsen JH.

2002. Cancer incidence and magnetic field exposure in

industries using resistance welding in Sweden. Occup

Environ Med 59(7):481–486.

IARC. 2002. Non-ionizing Radiation, Part 1: Static and Extremely

Low-Frequency Electric and Magnetic Fields. IARC

Monogr Eval Carcinog Risk Hum 80. 

Ivancsits S, Diem E, Jahn O, Rudiger HW. 2003a. Age-related

effects on induction of DNA strand breaks by intermittent exposure to electromagnetic fields. Mech Ageing

Dev 124(7):847–850.

Ivancsits S, Diem E, Jahn O, Rudiger HW. 2003b. Intermittent

extremely low frequency electromagnetic fields cause

DNA damage in a dose-dependent way. Int Arch Occup

Environ Health 76(6):431–436. 

Ivancsits S, Diem E, Pilger A, Rudiger HW, Jahn O. 2002.

Induction of DNA strand breaks by intermittent exposure

to extremely-low-frequency electromagnetic fields in

human diploid fibroblasts. Mutat Res 519(1-2):1–13.

Löscher W, Mevissen M. 1995. Linear relationship between flux

density and tumor co-promoting effect of prolonged magnetic field exposure in a breast cancer model. Cancer Lett

96(2):175–180.

Neutra RR, Del Pizzo V, Lee GM. 2002. An Evaluation of the

Possible Risks from Electric and Magnetic Fields (EMFs)

from Power Lines, Internal Wiring, Electrical Occupations

and Appliances. Oakland, CA:California EMF Program.

A 726 VOLUME 113 | NUMBER 11 | November 2005 • Environmental Health Perspectives

Perspectives Correspondence

The correspondence section is a public forum and, as such, is not peer-reviewed. EHP is not responsible

for the accuracy, currency, or reliability of personal opinion expressed herein; it is the sole responsibility of

the authors. EHP neither endorses nor disputes their published commentary.
Available: http://www.dhs.ca.gov/ehib/emf/RiskEvaluation/

riskeval.html [accessed 11 October 2005].

NIEHS. 1998. Assessment of Health Effects from Exposure to

Power-Line Frequency Electric and Magnetic Fields.

Working Group Report (Portier C, Wolfe M, eds). NIH

publcation no. 98-3981. Research Triangle Park,

NC:National Institute of Environmental Health Sciences.

Available: http://www.niehs.nih.gov/emfrapid/html/

WGReport/WorkingGroup.html [accessed 6 October

2005].

Siemiatycki J, Richardson L, Straif K, Latreille B, Lakhani R,

Campbell S, et al. 2004. Listing occupational carcinogens.

Environ Health Perspect 112:1447–1459.

Thun-Battersby S, Mevissen M, Löscher W. 1999. Exposure of

Sprague-Dawley rats to a 50-Hertz, 100-μTesla magnetic

field for 27 weeks facilitates mammary tumorigenesis in

the 7,12-dimethylbenz[a]-anthracene model of breast

cancer. Cancer Res 59(15):3627–3633.

Tynes T, Klaeboe L, Haldorsen T. 2003. Residential and occupational exposure to 50 Hz magnetic fields and malignant

melanoma: a population based study. Occup Environ

Med 60(5):343–347.

Villeneuve PJ, Agnew DA, Johnson KC, Mao Y, Canadian

Cancer Registries Epidemiology Research Group. 2002.

Brain cancer and occupational exposure to magnetic

fields among men: results from a Canadian populationbased case-control study. Int J Epidemiol 31(1):210–217.

Weiderpass E, Vainio H, Kauppinen T, Vasama-Neuvonen K,

Partanen T, Pukkala E. 2003. Occupational exposures

and gastrointestinal cancers among Finnish women.

J Occup Environ Med 45(3):305–315.

ELF MFs: Straif et al. Respond

Mild et al. suggest that we should have

included magnetic fields at extremely low

frequencies (ELF MFs) in our listing of

occupational carcinogens (Siemiatycki et al.

2004). We acknowledge that ELF MFs have

been classified as “possibly carcinogenic to

humans” (Group 2B) by the Monographs

Programme of the International Agency for

Research on Cancer (IARC 2002) and that

there is significant occupational exposure,

thereby meeting our operational criterion

for inclusion as a possible occupational carcinogen. However, the nature of the evidence that led to the IARC classification

complicates the designation of ELF MFs as

an occupational carcinogen.

For our article (Siemiatycki et al. 2004),

we drew on the evaluations of the IARC

Monographs Programme. Each evaluation

was based on data that were available at the

time of the deliberations of the working

group. We supplemented the evaluation by

adding information on major occupational

exposure circumstances and on the cancer

sites affected. For some carcinogens, notably

those evaluated recently, such information

was explicitly mentioned in the published

monograph, but for others it was based on

our expert judgment.

For ELF MFs, the IARC evaluation of

“possibly carcinogenic” was founded on a

determination that there was limited evidence of carcinogenicity in humans based

on its effects on childhood leukemia and

“inadequate evidence” in experimental animals (IARC 2002). In contrast with an

earlier evaluation [National Institute of

Environmental Health Sciences (NIEHS)

1998], the IARC Working Group considered

that studies conducted among adults, at work

or elsewhere, did not provide consistent

enough and strong enough evidence to support an evaluation of carcinogenicity. There is

no clear-cut way to classify an exposure that

has only been demonstrated to be carcinogenic (albeit group 2B) in children, but also

occurs among workers. Although we decided

not to include ELF MFs in our tables of

occupational carcinogens (Siemiatycki et al.

2004), we could have done so with a footnote

to explain that the evidence supporting that

evaluation was based on children.

Mild et al. also discuss the evidence on

the carcinogenic effects of ELF MFs that has

arisen since 2002. Although we agree that

some of these studies may substantially contribute to an evaluation of the carcinogenic

effects of ELF MFs, it was not in the scope

of our work to evaluate new information and

update the evaluations on all of the agents

reviewed. The World Health Organization

(WHO) will be holding a meeting of an

Environmental Health Criteria Task Group

in October 2005; this task group will evaluate the health effects of ELF MFs (including

cancer and noncancer outcomes). We anticipate that they will review the recent evidence

in conjunction with the evaluation of the

2002 IARC Monograph. The WHO

Environmental Health Criteria document on

ELF MFs should be published shortly after

this meeting.

The authors declare they have no competing

financial interests.

Kurt Straif

Elisabeth Cardis

Paolo Boffetta

International Agency for Research on Cancer

Lyon, France

Marie-Claude Rousseau

INRS-Institut Armand-Frappier

Université du Québec

Laval, Québec, Canada

Jack Siemiatycki

Université de Montréal

Montréal, Québec, Canada

E-mail: j.siemiatycki@umontreal.ca

REFERENCES

IARC. 2002. Non-ionizing Radiation, Part 1: Static and

Extremely Low-Frequency Electric and Magnetic Fields.

IARC Monogr Eval Carcinog Risk Hum 80. 

NIEHS. 1998. Assessment of Health Effects from Exposure to

Power-Line Frequency Electric and Magnetic Fields.

Working Group Report (Portier C, Wolfe M, eds). NIH publication no. 98-3981. Research Triangle Park, NC:National

Institute of Environmental Health Sciences. Available:

http://www.niehs.nih.gov/emfrapid/html/WGReport/

WorkingGroup.html [accessed 6 October 2005].

Siemiatycki J, Richardson L, Straif K, Latreille B, Lakhani R,

Campbell S, et al. 2004. Listing occupational carcinogens. Environ Health Perspect 112:1447–1459.

The NAS Perchlorate Review:

Second-Guessing the Experts

The Committee to Assess the Health

Implications of Perchlorate Ingestion

[National Academy of Sciences (NAS)]

released its final report [National Research

Council (NRC) 2005] in January 2005,

recommending a reference dose (RfD) for

perchlorate of 0.0007 mg/kg-day. In a commentary published online on 25 May 2005,

Ginsberg and Rice (2005) criticized the adequacy of the NAS committee’s scientific

deliberations, mischaracterizing the studies

reviewed by the committee and secondguessing its conclusions. Ginsberg and Rice

(2005) implied that the U.S. Environmental

Protections Agency’s (EPA’s) previous draft

RfD of 0.00003 mg/kg-day (U. S. EPA

2002)—and by inference the Massachusetts

perchlorate risk assessment [Massachusetts

Department of Environmental Protection

(Mass DEP) 2004] that mirrored the U.S.

EPA’s approach and which Ginsberg and

Rice peer reviewed—is more scientifically

defensible. 

The NAS committee was composed of

15 leading physicians and scientists with

combined range of expertise to evaluate

every scientific aspect of the perchlorate

database and of the U.S. EPA’s assessment

of that database. The makeup of this committee and its credentials are available on

the NAS website (NAS 2004). The NAS

committee studied and deliberated for more

than 15 months before issuing its report.

Those deliberations included three public

meetings during which it accepted verbal

and/or written comments from the U.S.

EPA, other government agencies, industry,

states, environmental groups, and attorneys.

After careful study and consideration of the

scientific studies that formed the basis for

the U.S. EPA’s 2002 draft RfD as well as

the 2004 Massachusetts risk assessment

(Mass DEP 2004), the NAS committee

considered 

several of the animal studies ... to be flawed in

their design and execution. Conclusions based on

those studies, particularly the neurodevelopmental

studies, were not supported by the results of the

studies.

Although Ginsberg and Rice (2005)

implied that the NAS committee should

have considered the threshold for measurable

iodine uptake inhibition “adverse” and that

the NAS inadvertently left out the “A” in

NOAEL (no observed adverse effect level),

the committee decisively stated that “inhibition of iodide uptake by the thyroid clearly is

not an adverse effect.” The committee carefully considered the issue of a NOEL (no

observed effect level) and a NOAEL. Based

Environmental Health Perspectives • VOLUME 113 | NUMBER 11 | November 2005 A 727

Correspondence
on a clinical study of patients receiving 

perchlorate long term, the NAS established

the NOAEL as 0.4 mg/kg-day (57 times

higher than its identified NOEL). 

Ginsberg and Rice (2005) further

expressed concerns regarding perchlorate in

breast milk and the subsequent possibility of

decreased breast milk iodine, citing Kirk

et al. (2005) and Gibbs (2004). Kirk et al.

(2005) reported perchlorate and iodide levels

in breast milk samples and noted that “if we

take all the available data, there is no meaningful correlation between the perchlorate

and iodide levels in breast milk.” The study

from Chile that Ginsberg and Rice refer to as

Gibbs (2004) is now published as Tellez

et al. (2005). The study found that iodine

nutrition of pregnant women in Chile is very

similar to that in the United States. Tellez

et al. (2005) found no maternal or neonatal

perchlorate-related thyroid effects or

decreases in breast milk iodine with perchlorate doses spanning the 0.0007–0.007

mg/kg-day range.

Ginsberg and Rice (2005) argued that

perchlorate database deficiencies require an

additional uncertainty factor of 3–10 because

of key data gaps, citing breast milk concerns

and the extrapolation from a 14-day exposure study to chronic exposure. The NAS

committee (NRC 2005) considered this and

concluded that 

if inhibition of iodide uptake by the thyroid is

duration-dependent, the effect should decrease

rather than increase with time, because compensation would increase the activity of the sodiumiodide symporter and therefore increase iodide

transport into the thyroid.

Evidence has subsequently shown this to be

the case (Braverman et al. 2005).

The California EPA perchlorate risk

assessment (California EPA 2004) relied on

the same studies as the NRC report (NRC

2005). The “point of departure” was based

on iodine uptake inhibition by Greer et al.

(2002), and a total uncertainty factor of 10

was applied to account for interindividual

variability. After reviewing the NRC report

(NRC 2005), the California EPA elected

not to change its risk assessment or public

health goal (California EPA 2005).

In summary, the concerns presented by

Ginsberg and Rice (2005) have already been

addressed thoroughly by experts on perchlorate and thyroid toxicology and were found

to be unsubstantiated. The NAS committee

and other experts came to this conclusion

based on a comprehensive review of the science in the field, not based entirely on an

individual study, which has been mischaracterized by Ginsberg and Rice.

Kerr-McGee Chemical LLC previously manufactured ammonium perchlorate at Henderson,

Nevada, and currently is remediating perchlorate at that site. J.G. has co-authored several

perchlorate studies, as has S.H.L. S.H.L. is a consultant to companies that manufacture and/or use

perchlorates. A.E. works with S.H.L. at

Consultants in Epidemiology & Occupational

Health, LLC. 

John P. Gibbs

Kerr-McGee Shared Services LLC

Oklahoma City, Oklahoma

E-mail: jpgibbs@kmg.com

Arnold Engel

Steven H. Lamm

Consultants in Epidemiology &

Occupational Health, LLC

Washington, DC 

REFERENCES

Braverman LE, He X, Pino S, Cross M, Magnani B, Lamm SH,

et al. 2005. The effect of perchlorate, thiocyanate, and

nitrate on thyroid function in workers exposed to perchlorate long-term. J Clin Endocrinol Metab 90(2):700–706.

California EPA (Environmental Protection Agency). 2004.

Public Health Goals for Perchlorate in Drinking Water.

Available: http://www.oehha.org/water/phg/pdf/

finalperchlorate31204.pdf [accessed 21 June 2005].

California EPA (Environmental Protection Agency). 2005.

State’s Drinking Water Goal For Perchlorate Consistent

With Findings of Major Federal Study. Available: http://

www.oehha.ca.gov/public_info/press/perchloratepressrel040105.pdf [accessed 21 June 2005].

Gibbs JP. 2004. Chronic Environmental Exposure to Perchlorate

in Drinking Water and Thyroid Function during Pregnancy

and the Neonatal Period. 8 August 2004 Update. Letter to

Richard Johnston, Chair NAS Perchlorate Committee, from

John P. Gibbs, Kerr-McGee Corp.

Ginsberg G, Rice D. 2005. The NAS perchlorate review: questions remain about the perchlorate RfD. Environ Health

Perspect 113:1117–1119; doi:10.1289/ehp.8254 [Online

25 May 2005].

Greer MA, Goodman G, Pleus RC, Greer SE. 2002. Health effects

assessment for environmental perchlorate contamination:

the dose response for inhibition of thyroidal radioiodine

uptake in humans. Environ Health Perspect 110:927–937.

Kirk AB, Martinelango PK, Tian K, Dutt, A, Smith EE, Dasgupta

PK. 2005. Perchlorate and iodide in dairy and breast milk.

Environ Sci Technol 39:2011–2017.

Mass DEP (Massachusetts Department of Environmental

Protection). 2004 Final Draft. Perchlorate Toxicological

Profile and Health Assessment. Available: http://www.

mass.gov/dep/ors/files/perchlor.pdf [accessed 22 June

2005].

NAS (National Academy of Sciences). 2004. Committee to

Assess the Health Implications of Perchlorate Ingestion.

Available: http://www4.nas.edu/cp.nsf/Projects%20_

by%20_PIN/BEST-K-03-05-A?OpenDocument [accessed

21 June 2005].

NRC (National Research Council). 2005. Health Implications

of Perchlorate Ingestion. Washington, DC:National

Academies Press.

Tellez RT, Michaud P, Reyes C, Blount BC, Van Landingham

CB, Crump KS, et al. 2005. Long-term environmental exposure to perchlorate through drinking water and thyroid

function during pregnancy and the neonatal period.

Thyroid 15(9):963–975.

U.S. EPA. 2002. Perchlorate Environmental Contamination:

Toxicological Review and Risk Characterization. External

Review Draft. NCEA-1-0503. Washington, DC:National

Center for Environmental Assessment, Office of Research

and Development.

The NAS Perchlorate Review:

Adverse Effects?

Ginsberg and Rice (2005) argued that the

reference dose for perchlorate of 0.0007

mg/kg per day recommended by the National

Academy of Sciences (NAS) Committee to

Assess the Health Implications of Perchlorate

Ingestion is not adequately protective. As

members of the committee, we disagree.

Ginsberg and Rice (2005) based their

conclusion on three points. The first

involves the designation of the point of

departure as a NOEL (no observed effect

level) versus a LOAEL (lowest observed

adverse effect level). The committee chose as

its point of departure a dose of perchlorate

(0.007 mg/kg per day) that, when given for

14 days to seven normal subjects, did not

cause a statistically significant decrease in the

group mean thyroid iodide uptake (Greer

et al. 2002). Accordingly, the committee

considered it a NOEL. Ginsberg and Rice

(2005) focused on the fact that only seven

subjects were given that dose; they seem to

say that attention should be paid only to the

results in those subjects in whom there was a

decrease in thyroid iodide uptake and that

the results in those in whom there was no

decrease or an increase should be ignored.

They considered the dose to be a LOAEL

because of the decrease in uptake in those

few subjects. It is important to note that a

statistically significant decrease of, for example, 5% or even 10% would not be biologically important and, more important, would

not be sustained. For example, in another

study (Braverman et al. 2004), administration of 0.04 mg/kg per day to normal subjects for 6 months had no effect on thyroid

iodide uptake when measured at 3 and

6 months, and no effect on serum thyroid

hormone or thyrotropin concentrations

measured monthly. [Inspection of Figure 5A

in Greer et al. (2002) suggests that this dose

would inhibit thyroid iodide uptake by

about 25% if measured at 2 weeks.] 

The second issue involves database

uncertainty. In clinical studies, perchlorate

has been administered prospectively to

68 normal subjects for 2 weeks to 6 months.

In one study (Brabant et al. 1992), a dose of

9.2 mg/kg per day for 4 weeks had no effect

on thyroid function. In occupational studies,

doses as high as 0.5 mg/kg per day had no

effect on thyroid hormone or thyrotropin

production in workers. In epidemiologic

studies, there were no abnormalities in

growth or thyroid function in children

exposed life-long to 100–120 μg perchlorate

per liter of drinking water, or in pregnant

women and newborn infants similarly

exposed. Given the choice of a nonadverse

effect (inhibition of iodide uptake by the

thyroid) as the point of departure and the

multiple studies in which doses of perchlorate much higher than 0.007 mg/kg per day

had no effect on any aspect of thyroid function, the committee did not apply a database

uncertainty factor. 

A 728 VOLUME 113 | NUMBER 11 | November 2005 • Environmental Health Perspectives

Correspondence
Finally, Ginsberg and Rice (2005) argued

that inhibition of thyroid iodide uptake is

adverse. That conclusion assumes that any

acute inhibition would be sustained, so thyroid

hormone production would decrease. That is

not the case. There is remarkable compensation

for even substantial reductions in thyroid

iodide uptake—and thyroid hormone production. As noted above, subjects given

0.04 mg/kg per day for 6 months and

9.2 mg/kg per day for 4 weeks—doses that certainly would inhibit thyroid iodide uptake for a

few weeks—had no decrease in serum thyroid

hormone or increase in serum thyrotropin concentrations (the hallmark of even mild hypothyroidism). Short-term inhibition of thyroid

iodide uptake is not an adverse effect; it has no

adverse consequences because there is rapid

compensation mediated by several independent

processes. One of these processes is up-regulation of the thyroid sodium-iodide transport system, as a result of intrathyroidal iodide

deficiency. The second, should there be even a

very small decrease in thyroid hormone production, is an increase in thyrotropin secretion,

resulting in overall stimulation of the thyroid

gland. Analyses of the effects of any substance

on thyroid function must take these compensatory processes into account, particularly the

fact that the effect of any substance that inhibits

thyroid function will diminish with time. Only

if all of these mechanisms fail will there be

hypothyroidism, the first adverse effect in the

continuum of effects resulting from perchlorate

ingestion. If there is no inhibition of iodide

uptake to begin with, there will be no other

changes in thyroid function at any time.

We believe that the committee’s recommended reference dose of 0.0007 mg/kg

per day provides a wide margin of safety for

all subjects of all ages.

The authors declare they have no competing

financial interests.

Richard B. Johnston Jr.

University of Colorado School of Medicine

Denver, Colorado

Richard Corley

Pacific Northwest National Laboratory 

Richland, Washington

Linda Cowan

University of Oklahoma Health 

Sciences Center 

Oklahoma City, Oklahoma

Robert D. Utiger

Harvard Medical School 

Boston, Massachusetts

E-mail: rutiger@partners.org 

REFERENCES

Brabant G, Bergmann P, Kirsch CM, Kohrle J, Hesch RD,

von zur Muhlen A. 1992. Early adaptation of thyrotropin

and thyroglobulin secretion to experimentally decreased

iodide supply in man. Metabolism 41:1093–1096. 

Braverman LE, He X, Pino S, Magnani B, Firek A. 2004. The

effect of low dose perchlorate on thyroid function in normal volunteers [Abstract]. Thyroid 14:691.

Ginsberg G, Rice D. 2005. The NAS perchlorate review: questions remain about the perchlorate RfD. Environ Health

Perspect 113:1117–1119; doi:10.1289/ehp.8254 [Online

25 May 2005].

Greer MA, Goodman G, Pleus RC, Greer SE. 2002. Health effects

assessment for environmental perchlorate contamination:

the dose response for inhibition of thyroidal radioiodine

uptake in humans. Environ. Health Perspect 110:927–937.

The NAS Perchlorate Review:

Is the RfD Acceptable?

Risk assessors should always carefully evaluate whether a given reference dose (RfD) is

the most appropriate choice for assessing

risk. In the case of perchlorate, Ginsberg

and Rice (2005) suggested that the RfD

proposed by the National Research Council

(NRC) is inappropriate because the NRC

did not thoroughly evaluate the underlying

science. However, we suggest that the NRC

RfD is inappropriate because of the NRC’s

“unconventional” approach.

In contrast to Ginsberg and Rice (2005),

we applaud the insightful and conclusive discussion of the science of perchlorate and the

thyroid by the NRC (2005). The NRC concluded that human studies are the most relevant for risk assessment, and that the thyroid

has a remarkable ability to compensate for

iodine deficiency, so that hypothyroidism

would be the first observed adverse effect. By

definition, this is perchlorate’s critical effect

(Faustman and Omenn 2001), although

U.S. Environmental Protection Agency

(EPA) methods allow for the use of a known

and immediate precursor (the choice of

immediate precursor is based on practice of

using the highest no observed adverse effect

level (NOAEL) of the critical effect and is

codified in several places (e.g., Barnes and

Dourson 1988, p. 473). The NRC also concluded that in healthy adults the perchlorate

dose required to cause hypothyroidism

would be > 0.4 mg/kg-day.

In risk assessment parlance, this dose

would be a NOAEL of the critical effect. The

practice of risk assessment allows us to draw

conclusions about public health in the absence

of observable data and in the presence of scientific uncertainty. The traditional practice of

developing RfD, a dose–response part of risk

assessment (Barnes and Dourson 1988),

would suggest two possible approaches to

developing an RfD from the perchlorate data.

The first would be to use the NOAEL of the

critical effect from an adult population and

apply uncertainty factors to account for sensitive populations and for lack of precision in

defining a NOAEL. The second approach

would be to use the NOAEL of an immediate precursor effect in a sensitive population

and apply appropriate uncertainty factors.

Using the first approach with the NRC

NOAEL, the RfD would lie in the range of

0.04–0.004 mg/kg-day depending on the

choice of uncertainty factor. Using the second approach, a NOAEL of 0.005 mg/kgday (Gibbs et al. 2004) can be identified

from thyroid hormone and goiter data in a

sensitive population. The RfD based on this

approach would lie near the value of

0.002 mg/kg-day proposed by Strawson

et al. (2004). 

In contrast, the approach the NRC actually used was a nonstandard approach for

developing an RfD based on the inhibition

of iodine uptake, a distant precursor to the

critical effect. This nonstandard approach

yields a safe dose, but it is not an RfD, by

definition, because, according to the NRC’s

own scheme, it is not based on the critical

effect or its known and immediate precursor. 

We continue to advocate that the best

risk assessment approach for perchlorate is to

use data collected from sensitive populations

such as children and, in particular, the published and ongoing work in Chile. This is

consistent with the NRC’s conclusion that

the data from Chile could be considered in

the evaluation of the U.S. experience with

perchlorate in drinking water (NRC 2005).

Specifically, the Chilean experience (Crump

et al. 2000; Tellez et al. 2005) can be used to

help frame the public debate in the United

States, which suggests perchlorate water standards as low as 1 ppb. In Chile, perchlorate

water concentrations of 100–120 ppb do not

result in an exposure that would inhibit

iodine uptake inhibition in adults. In fact,

these concentrations have not caused any

adverse effects in pregnant women, neonates,

or older children exposed chronically.

Following traditional RfD methods and

using data from a sensitive human population results in an RfD that can be used with

high confidence in the United States.

Toxicology Excellence for Risk Assessment

(TERA) is a nonprofit organization dedicated to

the best use of toxicity data for risk values.

Joan Strawson

Michael L. Dourson

Qiyu (Jay) Zhao

Toxicology Excellence for Risk Assessment

Cincinnati, Ohio

E-mail: dourson@tera.org

The authors have collectively studied the

toxicity of perchlorate since 1991 on behalf of

U.S. EPA and the nonprofit corporation

Toxicology Excellence for Risk Assessment at the

request of the Perchlorate Study Group.

Opinions expressed in this commentary, however,

reflect solely those of the authors and not of any

organization or other individual. Resources to

support this technical commentary were provided

by the developmental reserve fund of TERA.

Environmental Health Perspectives • VOLUME 113 | NUMBER 11 | November 2005 A 729

Correspondence
REFERENCES

Barnes DG, Dourson ML. 1988. Reference dose (RfD): description and use in health risk assessments. Regul Toxicol

Pharmacol 8:471–486.

Crump C, Michaud P, Tellez R, Reyes C, Gonzalez G,

Montgomery EL, et al. nction in newborns or school-age

children? J Occup Environ Med 42: 603–612.

Faustman EM, Omenn GS. 2001. Risk Assessment. In: Casarett

and Doull’s Toxicology: The Basic Science of Poisons

(Klaassen CD, ed.). 6th ed. New York:McGraw-Hill, 92.

Gibbs JP, Narayanan L, Mattie DR. 2004. Crump et al. study

among school children in Chile: subsequent urine and

serum perchlorate levels are consistent with perchlorate

in water in Taltal. J Occup Environ Med 46(6):516–517.

Ginsberg G, Rice D. 2005. The NAS perchlorate review: questions remain about the perchlorate RfD. Environ Health

Perspect Environ Health Perspect 113:1117–1119;

doi:10.1289/ehp.8254 [Online 25 May 2005].

NRC (National Research Council). 2005. Health Implications of

Perchlorate Ingestion. Washington, DC:National

Academies Press. 

Strawson J, Zhao Q, Dourson M. 2004. Reference dose for

perchlorate based on thyroid hormone change in pregnant women as the critical effect. Regul Toxicol

Pharmacol 39:44–65.

Tellez RT, Michaud P, Reyes C, Blount BC, Van Landingham

CB, Crump KS, et al. 2005. Long-term environmental exposure to perchlorate through drinking water and thyroid

function during pregnancy and the neonatal period.

Thyroid 15(9):963–975.

The NAS Perchlorate Review:

Ginsberg et al. Respond

We would like to respond to the comments from several members of the NAS

perchlorate panel (Johnston et al.) and

from two other groups (Gibbs et al.,

Strawson et al.). These letters were in

response to our commentary published in

EHP (Ginsberg and Rice 2005). The letters take an opposing viewpoint but do not

invalidate our main assertions that a) the

low dose reported in the Greer et al. study

(Greer et al. 2002) does in fact demonstrate a majority of subjects with the perchlorate-induced effect; b) there is the

potential for greater perchlorate vulnerability in pregnant women and newborns

than in the general population; and

c) inhibition of iodide uptake is a key step

in the perchlorate toxicodynamic pathway,

with moderate levels of uptake inhibition

potentially sufficient to produce adverse

effects in sensitive subgroups. 

The low dose reported by Greer et al.

(2002) was termed a no observable effect

level (NOEL) by the National Research

Council (NRC 2005). We disagreed with

this view in our commentary because four

of seven individuals at this dose showed

the characteristic perchlorate-induced

suppression of iodine uptake. Johnston

et al. claim that we ignored the nonresponders when we described the low dose

in the Greer study (Greer et al. 2002) as

an effect level. We did not disregard these

subjects, but we pointed out that they

segregate out as a subgroup who appear

to be less sensitive to the perchlorate

effect and have low baseline values. We

further pointed out that, because of the

small sample size (n = 7), there is very little statistical power to detect an effect at

Greer et al.’s low dose (0.007 mg/kg/day)

given the variability in response. Rather

than simply relying on a weak test of significance, our closer inspection of the

data indicated that the majority of the

low-dose subjects were responders. When

the results are organized categorically into

responders and nonresponders, it is evident that the low dose is part of the dose–

response continuum with no evidence of

a threshold: 0.5 mg/kg/day, 9 responders

out of 9 subjects; 0.1 mg/kg/day, 10

responders out of 10 subjects; 0.02

mg/kg/day, 6 responders out of 10 subjects; and 0.007 mg/kg/day, 4 responders

out of 7 subjects. The lack of statistical

significance should not be used as

grounds for disqualifying what appears to

be a biologically significant response. 

Hydrogen sulfide provides a good

example for illustrating biologic versus

statistical significance. In a key study,

Jappinen et al. (1990) found that an

inhaled dose of hydrogen sulfide did not

cause a statistically significant effect on

airway parameters in a group of 10 subjects with asthma. However, when these

data were used by the Agency for Toxic

Substances and Disease Registry (ATSDR)

to set a public health benchmark (the

acute minimum risk level), the fact that 2

of the 10 asthmatics were responders was

sufficient for this dose to be considered a

critical effect level (ATSDR 1999). The

perchlorate low-dose responders should

not be ignored, just as the hydrogen sulfide low-dose responders were not

ignored. 

Although the NRC considered Greer

et al.’s (2002) low dose a NOEL, like us,

the U.S. Environmental Protection

Agency (EPA) draft assessment (U.S. EPA

2002) and a risk assessment by the

Massachusetts Department of Environmental Protection (Mass DEP 2004) considered this dose to be a LOAEL (lowest

observed adverse effect level). The

California EPA conducted a benchmark

dose analysis on the data published by

Greer et al. (2002), finding

0.0037 mg/kg/day (approximately 2-fold

below Greer et al.’s low dose) the critical

point of departure for standard setting

(California EPA 2004). 

Strawson et al. make the argument that

the critical adverse effect of perchlorate is

hypothyroidism. It is important to understand that clinical hypothyroidism is not

the critical end point for derivation of the

perchlorate RfD. Subclinical hypothyroidism in pregnant women can result

in adverse nervous system effects in offspring (Zoeller et al. 2002), including

decreased IQ (Haddow et al. 1999).

Perchlorate’s inhibition of iodine uptake

increases the risk for hypothyroidism,

which even if subclinical, may still be associated with neurodevelopmental effects. 

The rebuttal letters (Gibbs et al.,

Johnston et al., and Strawson et al.) consider inhibition of iodine uptake a nonadverse effect because it is only temporary

and because compensatory homeostatic

mechanisms would not allow actual

declines in thyroid hormone to occur.

They cite an abstract by Braverman et al.

(2004) to demonstrate that the perchlorate

effects seen by Greer et al. (2002) disappear

upon longer-term (6 month) exposure. As

we pointed out in our commentary

(Ginsberg and Rice 2005), the study by

Braverman et al. (2004) has not been published or peer reviewed and involves small

numbers of subjects. It is unclear whether

there was sufficient statistical power to see

the perchlorate effect. Since the publication of our commentary we became aware

of a different study by this same group

(Braverman et al. 2005). Gibbs et al. also

mentioned this study. In contrast to their

abstract (Braverman et al. 2004),

Braverman et al. (2005) show iodine

uptake inhibition in relatively young male

Caucasian workers who had a median perchlorate exposure period of 5.9 years. The

dose response for these long-term perchlorate workers was similar to that shown for

subjects exposed to perchlorate for 2 weeks

(Greer et al. 2002). This suggests that,

contrary to the NRC report (NRC 2005)

and Braverman et al. (2004), perchlorate

does not lose its potency to inhibit iodide

uptake under conditions of long-term

exposure. 

The fact that the workers in the study

by Braverman et al. (2005) did not have

indications of thyroid deficiency suggests

that healthy workers can compensate for

this type of biochemical impairment.

This is likely due to several factors,

including sufficient iodide and hormone

reserves in these workers. However, it is

uncertain that perchlorate-induced

impairment of iodine uptake would be

compensated for in all members of the

population. In particular, a substantial

percentage of the general public has low

iodine intake [Centers for Disease

Control and Prevention (CDC) 2000;

Hollowell et al. 1998], pregnant women

can be at greater risk for iodine deficiency

(Azizi et al. 2003), and the neonate

appears to have minimal stores of thyroid

A 730 VOLUME 113 | NUMBER 11 | November 2005 • Environmental Health Perspectives

Correspondence
hormone (Delange 1998; van den Hove

et al. 1999). In addition, the data of

Braverman et al. (2005) suggest up-regulation of the iodide symporter in these

workers, a protective mechanism that

may not exist in the fetus or neonate.

Infants have added susceptibility because

perchlorate is excreted into breast milk

and appears to inhibit iodine secretion

into breast milk (Kirk et al. 2005).

On this last point, the letter by Gibbs

et al. casts doubt on the relationship

between perchlorate and iodine levels in

breast milk by quoting from Kirk et al.

(2005): “If we take all the available data,

there is no meaningful correlation between

the perchlorate and iodide levels in breast

milk.” This is a case of selective quoting, as

the very next sentence states, “On the other

hand, for breast milk that contained

≥ 10 μg/L perchlorate, the iodide concentration expressed in milk is linearly related

to the reciprocal of perchlorate concentration.” Although we would agree that the

findings of Kirk et al. (2005) need to be

further explored, Gibbs et al.’s dismissal

of these findings—on the basis of an outof-context quote—is misleading. 

Strawson et al. claim in their letter that

the NRC used a nonstandard approach in

deriving the perchlorate RfD. Citing an

article by Barnes and Dourson (1988), they

state that there are two possible approaches

to developing an RfD: the use of a

NOAEL of a critical effect from an adult

population, or the use of the NOAEL of a

precursor effect in a sensitive population.

Barnes and Dourson (1988) did not discuss such a dichotomy of approaches, nor

did more recent U.S. EPA guidance (e.g.,

U.S. EPA 1991, 2002). In fact, IRIS (the

Intergrated Risk Information System; IRIS

2005) defines “critical effect” as “[T]he

first adverse effect, or its known precursor,

that occurs to the most sensitive species.”

There is no distinction in any of these documents made for critical end point being

chosen based on sensitive population, nor

is there discussion of “immediate precursor” versus other precursors, a distinction

made by Strawson et al. Therefore, the

assertion that the NRC used a nonstandard

approach in using a precursor event in a

nonsensitive population (adults) is not supported in U.S. EPA guidance (U.S. EPA

1991, 2002).

Also at issue are the uncertainty factors

that need to be applied to the data of

Greer et al. (2002) to derive a health-protective RfD. The NRC risk assessment

included a total 10-fold uncertainty factor

(NRC 2005). This factor is expected to

cover a lot of ground: variability in toxicokinetics and toxicodynamics among

healthy adults, variability caused by low

iodine uptake, pregnancy, neonatal vulnerabilities described above, and the data gaps

and temporal uncertainties described in

our commentary (Ginsberg and Rice

2005). Because of these factors, our scientific judgment is that a 10-fold uncertainty

factor is insufficient, which is the same

judgment arrived at in the U.S. EPA draft

assessment (U.S. EPA 2002) and in the

Massachusetts risk assessment (Mass DEP

2004). 

The letters of Gibbs et al. and

Strawson et al. allude to the Chilean data

set (Crump et al. 2000; Tellez et al. 2005)

as documenting that early life stages are

not especially affected by relatively high

exposure to perchlorate in drinking water.

If this were the case, it would decrease the

level of uncertainty contained in the risk

assessment. However, in our commentary

(Ginsberg and Rice 2005), we pointed out

the limitations of the Chilean data. It

requires extrapolation from an iodineenriched population in Chile to the

United States, which has considerably less

iodine intake. Further, nearly 5% of

school-age children and 15% of women of

childbearing age in the United States have

low iodine intake (CDC 2000; Hollowell

et al. 1998) these individuals are likely not

well represented by the Chilean data set.

Crump et al. (2000) show an association

between high perchlorate in drinking

water and family history of thyroid disease.

The fact that this association did not

extend to altered thyroid status in the children studied raises the possibility that

iodine supplementation efforts in recent

decades in Chile prevented the perchlorate

effect in current-day children (Crump

et al. 2000). This leaves open the question

of perchlorate-induced effects in children

in the United States whose iodine intake is

suboptimal. A follow-up study by Tellez

et al. (2005) reproduces some of the earlier

Chilean findings but shows that in spite of

very recent reductions in the iodide content of salt in Chile, iodine levels are still

approximately 2-fold higher there than in

the United States. The Chilean studies do

not remove the uncertainties present in the

perchlorate database. 

Our disagreement with the NAS perchlorate document (NRC 2005) and

with these letters centers around how a

no effect level is defined and how vulnerable life stages are factored into a risk

assessment. These authors recommend

stretching the definition of NOEL to

include a dose level in which the majority of the subjects demonstrate the perchlorate effect. Gibbs et al., Johnston

et al., and Strawson et al. also recommend using studies of healthy adults and

a poorly matched Chilean population to

dismiss the adverse nature of perchlorateinduced iodide uptake inhibition for vulnerable subgroups. As state risk assessors,

we strive to keep methods and judgment

consistent across all chemicals. Applying

that to perchlorate leads us to a different

analysis than what was presented by the

NAS and what is promoted in the letters

responding to our commentary (Ginsberg

and Rice 2005). 

The authors declare they have no competing

financial interests.

Gary Ginsberg

Connecticut Department of Public Health

Hartford, Connecticut

E-mail: gary.ginsberg@po.state.ct.us

Deborah Rice

Maine Bureau of Health

Augusta, Maine

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1999. Toxicological Profile for Hydrogen Sulfide. 

Azizi F, Aminorroya A, Hedayati M, Rezvanian H, Amini M,

Mirmiran P. 2003. Urinary iodine excretion in pregnant

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A 732 VOLUME 113 | NUMBER 11 | November 2005 • Environmental Health Perspectives

Correspondence

ERRATUM

In Figure 2D of Greer et al. [Environ

Health Perspect 110:927–937 (2002)],

there should have been seven subjects in

the 0.007 mg/kg-day group, but EHP

erroneously included an extra line (without symbols), indicating a nonexistent

eighth subject. This error was reproduced

in the commentary of Ginsberg and Rice

[Environ Health Perspect 113:1117–1119

(2005)] and was included in their argument that there was an inhibitory effect

overall in that dose group.

EHP regrets the error.

D 40

35

30

25

20

15

10

5

0

BV

24-hr RAIU (%123I administered)

E14 P15

Figure 2D.The 24-hr thyroid radioiodine uptake

(RAIU) at the baseline visit (BV) and on exposure

day 14 (E14) and postexposure day 15 (P15) for each

subject in the 0.007-mg/kg-day dose group.