## RiskAssessment 

## of Thyroid Follicular Cell Tumors

Hill,1 M. Pamela M. Hurley,' Rosenthal2 and Dharm V. 

### Sing2f

1Office of Prevention, Pesticides and Toxic Substances, and 2Office of Research and Development, U.S. Environmental Protection Agency, Washington, DC 20460 USA

Thyroid

### folliclar

### celi tumor arise inrodents frommutations, perturbations ofthyroidandpituitayhormone status with increased sution of thyroid cell growth by

### thyroid-stimulating hormone (TSH), oracombinationofthetwo. The onlykownhumanthyroidcarcinogenis ionizingradiation. It isnotknownforcertainwhether chemicals thataffect thyroidcell growth lead
to 

### human thyroid cancer. The U.S. Environmental ProtectionAgencyapplies the following science

### policypositions: 1) chemical inducedrodent thyroidtumors arepresumedtoberelevnt to humans; 2) wheninterspecies informationislacking thedefault is toasmecomparble carcinogenic

### senitivityinrodents andhumans; 3) adverserodentnoncancerthyroideffe due to chemically induced 

### thyroid-pituity disruption are presumed to be relevant to humans; 4) linear dose-response considerations are 

### applied to 

### thyroid cancer induced by chemical substaces that either do not

### disrupt thyroid functioning or lackmode ofaction information; 

### 5) nonlinear 

### thyroid cancer dose-response considerations are applied to chemicals that reduce 

### thyroidhormone levels, increase TSH and thyroid cell division, andare judged to lackmutanic 

### acivity, and 6) nonlinear 

### conideions maybe applied in thyroid cancerdose-response assessments on a caseby-case basis for chemicalls that disrupt 

### thyroid-pituitary functioning and demonstrate some mutagenic 

### activity. Requireddataforriskasessment

### purposes ismode ofaction information on 

### mutgenicity, increases in

### follicular

### cellgrowth (cell size andnumber) and

### thyroid

### glandweight, 

### thyroid-pituitary

### honrones, site ofaction, correlations between doses producing thyroid effects andcancer, and

### reversibilityofeffet when

### dosingceases. Key won iodide pump, microsomal

enzyme induction, 5'-monodeiodinase, ris assessment, thyroid follicular cell tumors, thyroid hormone (T4, T3), thyroid p ida, 

### throid-smulatinghormone (TSH), UDP glucuronosyl 

### trnsferase. Enwron

### Healt 

### Perspect106:447-457 

### (1998). 

### [Online 29

### June 1998] 

### hbtap//ehpnal.niehs.nihgo.ldo/1998/106p447457hiWlbsaract.html

The U.S. 

### Environmental Protection

### Agency 

### (EPA) conducts risk assessments on 

### chemi

### cals for carcinogenicity 

### under the 

### guidance provided in its cancer assessment 

### guidelines (1,2). From time to time, 

### scientificdevelopments cause 

### the agency to reexamine 

### procedures 

### that are 

### generally applied. That is 

### the

case

### with the review 

### of some chemicals that 

### have

### produced thyroid follicular cell tumors in 

### experimental animals. In 

### this paper, we 

### will present a summary 

### of 

### thyroid carcinogenesis and 

### describe the 

### procedures the
EPA 

### will use to 

### evaluate these tumors 

### and the data that are 

### needed to 

### make these 

### judgments. Experience in 

### applying the 

### thyroid 

### policy to a set 

### of

### pesticides has been 

### reported (3). The 

### proposed EPA cancer assessment 

### guidelines 

### () generallyoperate on the rebut

### table premise that 

### findings of 

### chemically induced cancer in 

### laboratory animals 

### signal potential hazards in humans. 

### Likewise, for 

### dose-response 

### analyses, the 

### guidelines first 

### call foruse ofthe most

### biologicallyappropriate means for dose 

### extrapolation. In the absence of such 

### knowledge, assessors are 

### directed toward the use of 

### default science 

### policy positions, either low-dose 

### linear, 

### nonlinear, orboth

### procedures. Male rat kidney tumors 

### due to 

### accumulation of ax2u

### globulinwere the 

### first instance in

### which the
EPA 

### developed generic 

### guidance for the
assessment 

### ofa

### specific tumor type 

### (4); 

### thyroidtumors are 

### the 

### second. Although the present 

### effort is 

### directed 

### specificallyat tumors 

### ofthe 

### thyroid follicular 

### cells, it is 

### recognized that endocrine
organs that secrete hormones into 

### the blood or 

### lymph 

### respond to stimuli via

common 

### pathways, and other organs may 

### develop tumors 

### bydisruption ofhormonal balance. 

### Therefore, it may be 

### possible that

some 

### ofthe lessons 

### learnedwith the 

### analysis 

### of

### thyroid follicular cell tumors 

### will be 

### applicable to other endocrine tumor sites in the future (5,6). In 1988, the EPA 

### developed a review ofthe existing science on 

### thyroid follicular cell 

### carcinogenesis and a 

### draft science 

### policy position covering the evaluation of chemicals that have induced 

### thyroid
tumors in 

### experimental animals. The external EPA Science 

### Advisory Board 

### approved the science review 

### (7) and 

### tentatively embraced the policy position that 

### dose-response relationships for some thyroid tumors could be assessed using nonlinear 

### considerations. After revision and a 

### sec

### ond review, 

### the 

### policy document was 

### final

### ized (8). This 

### paper presents the 

### underlying science policy for thyroid 

### follicular cell tumors. 

### Overview of Thyroid 

### Carcinogenesis Circulating thyroid hormone 

### determines the level of 

### operation of most cells of the 

### body (9); too much or too little 

### hormone results in 

### disease. Control of the 

### concentration 

### of this 

### endocrine hormone in the 

### blood is 

### mainly 

### regulated by a 

### negative feedback involving three organs: the thyroid 

### gland, which 

### produces 

### thyroid hormone, and the pituitary 

### gland and hypothalamus, which 

### respond to and 

### help maintain 

### optimal 

### levels ofthyroid hormone (Fig. 1). The 

### hypothalamus stimulates the 

### pituitary 

### through 

### thyrotropin-releasing hormone (TRH) to 

### produce 

### thyroid-stimulating hormone 

### (TSH), which then 

### prompts the thyroid 

### gland to 

### produce thyroid 

### hormone. The 

### stimulated thyroid actively transports 

### inorganic iodide into 

### the follicular cell and
converts it to an organic 

### formand then into 

### thyroid hormone 

### molecules, which can 

### influence target organs 

### throughout the body. 

### Thyroid hormone, in tissues 

### peripheral to the 

### thyroid, can 

### be converted from a less active thyroxine (T4) to a more active 

### triiodothyronine (T ) form. 

### Thyroid hormone is also 

### metaboized by the 

### liver, largely by 

### conjugation reactions, and 

### excreted into the bile. 

### Cells in the 

### hypothalamus and pituitary 

### glandrespond to 

### levels ofcirculating 

### thyroid hormone, such that 

### when 

### thyroid hormone levels are

### high, there is a 

### signal to 

### reduce 

### the output of TRH and TSH. Likewise, when 

### thyroid hormone levels are 

### reduced, the

Address correspondence to R.N. Hill, Office of Prevention, Pesticides and Toxic Substances, U.S. Environmental Protection Agency (7101), 401 M Street, S.W., Washington, DC 20460 USA. This paper is dedicated to the memory ofOrville E. Paynter, who began this project in 1985. Received 29 September 1997; accepted 27 February 1998.

Environmental Health Perspectives * Volume 106, Number 8, August 1998 447Reviews * Hill et at.

14 m:..



# ......

, ..

## U.

p. 

### -11X}

Exicndon

Figure 1. Hypothalamic-pituitary-thyroid axis. Abbreviations: TRH, thyrotropin-releasing hormone; TSH, thyroid stimulating hormone; T3, triiodothyronine; T4, thyroxine.



### hypothalamus and pituitary are 

### prompted to 

### deliver more TSH to 

### the 

### thyroid gland to increase 

### the output 

### of

### thyroid hormone. 

### This negative 

### feedback 

### loop helps the 

### body
to 

### respond to varying 

### demands for 

### thyroid hormone and to maintain 

### hormone homeostasis. 

### Circulating T4, 

### T3, and TSH can 

### readilybemonitored in 

### the serum

### ofexper

### imental animals and humans 

### by radioimmunoassay

### andserveas

### biomarkers ofexposure 

### and effect of agents 

### that 

### disrupt thy

### roid-pituitarystatus. In 

### mammals, when demands for more 

### thyroidhormone are 

### small, existing

### thyroid follicular cells can meet 

### the demand. With 

### increased 

### need, as a

### result ofcertain 

### chemical exposures or 

### iodide 

### deficiency, the 

### thyroid

### responds 

### by increasing 

### the size 

### (hypertrophy) and number 

### (hyperplasia) of 

### thyroid 

### follicular cells to 

### enhance hormone output. 

### With continued TSH 

### stimulation 

### there is 

### actual 

### enlargement of the 

### thyroid gland (goiter) 

### and, at 

### least in

### rodents, even

### tually neoplasia of the 

### thyroid follicular 

### cells. Since 

### TSH-producing pituitary 

### cells

are 

### also 

### stimulated, they too sometimes 

### undergo

### hyperplasiaand

### neoplasia.
For 

### details 

### about 

### thyroid follicular cell carcinogenesis, 

### consult 

### Hill et 

### al. 

### (7) and an 

### update ofthe science since 1988 (10), as

### well

asanumberof

### relevant reviews (11-25). Rich historical 

### literatureisalso

### valuable 

### (26-33).

Role 

### ofTSH in

### Rodent 

### Carcinogenesis
Several experimental 

### findings in rodents that perturb 

### thyroid-pituitary homeostasis and lead to elevated TSH levels 

### indicate the central role 

### ofTSH in inducing thyroid carcinogenic 

### effects: 1) 

### loss ofthyroid cells 

### through partial 

### thyroidectomy led to a 

### sustained 

### inability of 

### the 

### thyroid to meet the 

### demands for 

### thyroid hormone; 2) iodide deficiency decreased the thyroid's ability to synthesize adequate supplies of 

### thyroid 

### hormones; and 3) 

### transplantation ofpituitary tumors that autonomously secrete TSH added more of the trophic hormone to 

### graft recipients 

### (7). These experimental 

### manipulations were done in the absence of
any exogenous chemical treatment but demonstrate the seminal qualitative role that TSH plays in thyroid carcinogenesis. Quantitatively, its significance is demon

### stratedbythe correlation between the TSH 

### level 

### and the number of 

### tumors/gland in

an 

### initiation-promotion 

### study (15). If a goitrogenic stimulus that would 

### lead to 

### thyroid tumor 

### formation in rodents is removed early in 

### the process, effects

reverse toward normal 

### (34). 

### Likewise, if a goitrogenic stimulus is given in 

### conjunction with adequate amounts of exogenous 

### thyroid hormone 

### (35) or 

### after

### hypophysectomy to remove 

### TSH-secreting cells 

### (36), then 

### hypertrophy, hyperplasia, and tumors of 

### the 

### thyroid do not 

### develop. It follows 

### from these 

### observations that ifTSH levels

are 

### chronically 

### elevated, there will be 

### thyroid cell 

### hypertrophy, 

### hyperplasia, and

some 

### potential for 

### neoplasia, but under 

### conditions 

### where 

### thyroid-pituitary homeostasis is 

### maintained, the steps 

### leading to tumor 

### formation are not 

### expected to develop, and the 

### chances oftumor 

### development

are

### negligible.

Genetic Influences
Rodent studies indicate an 

### interplay between genetic and nongenetic events in the 

### development of 

### thyroid tumors. 

### Evidence indicates that carcinogenesis 

### often

### proceeds 

### through a 

### number ofopera

### tional steps: 

### initiation, promotion, and progression 

### (37). Initiation seems linked to genetic events 

### with 

### the induction of DNA 

### mutations, whereas promotion includes at least nongenetic events that lead to the expansion 

### of a clone 

### of initiated cells via 

### repeated cell 

### division. Progression is associ

### ated with the 

### accumulation of cell behaviors 

### (such as enzymatic 

### destruction ofbasement 

### membranes and increased 

### mobility) that allowcells to invade locally andmetastasize 

### distally, probably in part 

### due to still 

### other mutations. Some genetic influences do not result in mutations, but in changes in gene expression that can affect the car

### cinogenicprocess. Treatment regimens that 

### produce thyroidtumors inrodents canbe

### conceptualized in

### regard to initiation andpromotion. These steps

### donot themselvesdescribecarcinogenic mechanisms but, 

### instead, present a frameworkforviewingexperimental 

### findings. *In two-stage experiments in which a mutagenic agent such as radioactive iodide is followed 

### by treatment with a nonmutagenic goitrogen 

### (e.g., a chemical inhibitor of 

### thyroid hormone 

### synthesis), the first agent acts like an initiator and the secondbehaves as apromoter 

### (38).

*When treatment with a 

### goitrogen alone leads to tumor 

### formation, TSH increases cell division among 

### normal 

### cells, which leads to increases in the overall chance ofa spontaneous initiatingmutation, and then promotes the altered 

### cells, which retain responsiveness to 

### TSR; carcinogenesis in these cases would be free of 

### chemically inducedmutageniceffects 

### (39).

* Some 

### chemicals appear to

### have both initiating and promoting activity, as they are mutagenic in many test systems and have significant antithyroid activity (e.g., 

### 4,4'- oxydianiline) 

### (40).

* Still other agents, such as x irradiation 

### (41) and certain chemicals (e.g., some nitrosamines) (42), are definitely mutagenic but 

### lackintrinsicgoitrogenicactivity. These agents can easily initiate the carcinogenic process, but tumor formation wouldbe independent ofstrongpromotional activity from 

### antithyroid effects. TSH may stillplayapermissive role, as theseagents can induce cell injury and cell death, which lead to 

### reductions in 

### the output of 

### thyroid hormone and increases in 

### TSH-induced cell divisionofinitiated

### thyroidcells. It thus appears that thyroid cancer in experimental 

### animals may 

### be due to mutagenic influences that lead to DNA changes (X rays, 

### 1311, mutagenic 

### chemicals), to hormone perturbation that 

### leads to growth 

### stimulation, or both. Hormone perturbation directly increases the number of 

### thyroid cells 

### and 

### indirectly leads to mutations (partial 

### thyroidectomy, transplantation of TSH-secreting pituitary tumors, iodide deficiency, chemicals 

### inhibiting iodide 

### uptake by the 

### thyroid, chemicals inhibiting 

### thyroid peroxidase, chemicals inhibiting 

### release of thyroid hormone 

### from the thyroidgland, 

### chemicals damaging thyroid follicular

### cells, chemicals 

### inhibitingconversion 

### of 

### T4 to 

### T3, 

### chemicals increasing 

### hepatic thyroid hormone metabolism 

### and excre

### tion). In those cases where increases in cell number are

### dominant, the incitingagent or procedure may be seen as the carcinogenic 

### stimulus, but the proximate carcinogenic 

### influence is TSH. For those with a dominant mutagenic 

### influence, TSH may play

an 

### enhancing role in the carcinogenic
process. 

### Possible

### Mechanistic Steps The precise molecular steps in the carcinogenicprocess 

### leading to thyroid 

### follicularcell

cancer have not been totally elucidated, 

### althoughsignificant insights into theproblem

Volume 106, Number 8, August 1998 * Environmental Health Perspectives 448Reviews * Assessment of thyroid tumors



### have been 

### described (25,43). Normal cell 

### division in

### the

### thyroidseems to

### beaffectedby

an 

### interplay among 

### several mitogenic 

### factors, namely TSH, 

### insulin-like growth factor 1 

### (IGF-1), insulin, epidermal growth factor (EGF), and possibly fibroblast growth factor (FGF). 

### Stil other factors such as transforminggrowth 

### factor

, 

## (TGFP), certain interferons, and

### interleukin 1 mayinhibitgrowth. TSH communicates with the 

### cell's 

### interior

### byactivatingadenylate 

### cydase to raise lev

### els 

### ofcyclic AMP. It 

### also 

### functions through the 

### phosphatidyl-inositol/Ca2+ signal trans

### duction 

### cascade, which activates 

### phospholipase C. 

### This latter 

### system expresses 

### itself through two 

### pathways: inositol 

### triphosphate, which releases calcium 

### from cellular stores, 

### and 

### 1,2-diacylglycerol, which activates protein 

### kinase C. 

### Signal transduction continues 

### followingproteinkinase Cactivation

### through several steps, 

### including the ras

### protooncogene and various 

### kinases, culminating in the activation 

### ofnuclear transcription 

### factor genes 

### (e.g., 

### c-fs), which leads to 

### cellular 

### proliferation. 

### The 

### diacylglycerol pathway may account 

### for the 

### fact that the 

### phorbol ester tumor promoters, which increase protein kinaseC, alsostimulate thyroid

### celldivision. EGF, 

### insulin, and IGF-1 act 

### through tyrosine kinase 

### receptors. TSH increases EGF 

### binding to its receptor 

### and enhances cell division. IGF-1 

### and high doses of insulin may 

### influence the TSH receptor. 

### Iodide decreases 

### thyroid cell 

### adenylate 

### cyclase and calcium 

### levels, and reduced iodide enhances TSH 

### effectiveness. In sum, 

### the 

### actual control ofnormal 

### cell division in 

### follicular cells may, in 

### fact, represent some interaction 

### ofall these 

### factors and 

### possibly other

### growthregulatorysubstances. Under conditions of 

### thyroid-pituitary imbalance, there is no question that TSH 

### plays a 

### significant role in 

### stimulating DNA 

### synthesis and cell 

### proliferation; however, there is a controversy concerning the extent 

### that normal follicular 

### cells can 

### proliferate.
One 

### research group 

### claims that cells have 

### limited capacity to 

### respond to 

### the 

### growthinducing effects ofTSH 

### (44). In this case, tumor 

### formation would entail mutational steps that 

### free cells 

### fromtheir

### growth limiting 

### potential. Another group 

### of 

### investigators 

### thinks that 

### follicular cells are 

### innately heterogeneous, with some 

### of them 

### having
stem cell-like 

### proliferation 

### potential while others are more restricted 

### (45). The stem cell-like follicular cells would continue to 

### respond to TSH 

### stimulation and

### eventually give rise to tumors. It seems 

### possible that bothpositions 

### might

### actually

### apply. Neoplastic transformation appears to

occur in 

### single cells that then 

### expand clonally. Under 

### TSH 

### stimulation, the 

### yield of mutations thatmayinfluence transformation increases, even in the absence ofan increase in the mutation rateper cell. This is because 

### the repeated cell divisions lead to an 

### increased number of cells at 

### risk for 

### mutation, orrapid

### cell turnover leaves some spontaneous DNAdamageunrepaired. The precise genetic alterations that accumulate in 

### thyroid follicular cells 

### have not been clearly 

### established in humans or in 

### experimental systems, although mutations 

### involving the ras 

### protooncogene, the p53 tumor 

### suppressor gene, 

### and various chromosome 

### aberrations have been 

### report

### ed in 

### the follicular variety 

### of epithelial tumors. 

### These changes in gene expression 

### could lead to 

### uncontrolled cellular growth 

### and allow cells to attain the ability to 

### invade adjacent tissues and 

### metastasize (Fig. 2). For the 

### papillaryvarietyof

### thyroid 

### epithelial tumors, 

### changes in expression of 

### other factors have been 

### noted, namelyprotooncogenes PTC/ret, trk, and met 

### (25,43). Transformed rodent cells that are 

### stim

### ulated to 

### proliferate under 

### the influence of continuing 

### antithyroid stimulation retain their 

### responsiveness to TSH. 

### Interestingly, human 

### thyroid cancer 

### cells often 

### retain TSH receptors and the ability to respond to TSH, 

### although their receptors dissipate

as tumors 

### become more 

### anaplastic. Tumor cells 

### that attain 

### maximal malignant potential 

### usually lose their 

### dependence on TSH. 

### Although interesting 

### observations concerning 

### growth 

### regulation associated with thy

### roid carcinogenesis 

### have beenmade, 

### clearly

more

### workis

### needed.



### Human

### ThyroidCarcinogenesis Clinically manifest 

### thyroid cancer in humans in the United States is uncommon 

### and

### largely

### nonfatal; onlyabout 17,200 new
cases occur 

### each year 

### (an incidence rate 

### of 

### around 3 per 100,000 persons, with about 

### 1,200 deaths 

### annually (>90% 5-year sur

### vival, which constitutes 

### only around 0.5% 

### ofall cancer 

### deaths) 

### (46,47). In contrast to 

### clinically apparent 

### disease, small 

### occult 

### thyroid cancers are 

### noted at autopsy in a 

### small percentage 

### of persons in a 

### number 

### of surveys 

### and up to 

### about 50% in 

### other investi

### gations 

### (48,4p). The incidence in autopsy 

### studies is more 

### like that 

### noted in rats in 

### the National 

### Toxicology Program, 

### where about 0.4% ofcontrol rats are

### diagnosedwith 

### thyroid cancers at 2 years ofage (50). However, this 

### comparison is somewhat 

### misleading. Detailed 

### histological examinations of human and rodent 

### thyroids are not routine

### ly 

### performed by all investigators. 

### Histological criteria for tumors differ over time and across reviewers. In 

### addition, 

### thyroid follicular cell cancer in humans is most often diagnosed histologicly as a papillary 

### pattern and less often as a follicular pattern, TSH, insulin, IGF-1, EGF, FGF

ras, Chromosome aberrations of5,7 and 12. gap

Lossofheterozygosityat3p

roid (follicular) carcinogenesis. Abbreviations:

TSH, thyroid-stimulating hormone; IGF-1, insulinlike growth factor 1; EGF, epidermal growth factor; FGF, fibroblast growth factor; gsp, GTP-binding protein mutation.

whereas in rodents the follicular cell tumors

are of a follicular pattern. The aggressiveness

of tumors varies: rodent thyroid neoplasms rarely metastasize; human cancers frequently

metastasize. These differences regarding histology, along with the shortcomings of

information from descriptive and analytical epidemiologic investigations, help to emphasize the diffilculty in comparing

human and rodent cancer incidence data.

For years, the only known human thyroid carcinogen was x irradiation, which

caused an increase in papillary tumors
(41,51). It was questioned whether ionizing

radiation from diagnostic or therapeutic use

of 1311 was carcinogenic in humans (52,53), although more recently, children exposed to

radioiodine (1311) following the Chernobyl

reactor accident in the Ukraine have developed thyroid cancer; iodide deficiency is

also common in the region and may augment the response to 1311I (54). Most of the

human chemical carcinogens appear to be mutagenic and cause tumors in more than

one site; some are steroid hormones. To

date, no chemical has been identified as being carcinogenic to the human thyroid.

Rumans respond as do experimental animals in regard to short- and mid-term disturbances in thyroid functioning from various antithyroid stimuli such as iodide deficiency, partial thyroidectomy (surgically or 1311
induced), and goitrogenic chemicals (e.g.,
thionamides): when circulating thyroid hormone levels go down, the TSR level rises and

induces thyroid hypertrophy and hyperplasia.

Rowever, the long-term consequences of antithyroid action are harder to interpret,

and there is controversy regarding whether

the enlarged human thyroid gland undergoes

Environmental Health Perspectives * Volume 106, Number8, 

### August 1998 449 1

1

1Reviews * Hill et al.

conversion to cancer. 

### Thyroid enlargements and nodules have been 

### implicated as possi

### ble antecedents to 

### thyroid cancer in humans, but direct evidence of conversion 

### of 

### these lesions to 

### malignancy is 

### lacking. The 

### evidence that 

### does exist for possible conversion of 

### preneoplastic to 

### neoplastic lesions is 

### only 

### indirect in nature. Persons 

### who live in 

### iodide-deficient areas of the 

### worldare 

### unable to 

### synthesize 

### adequate levels of 

### thyroid 

### hormones; they develop elevated TSH 

### levels, very 

### enlarged thyroid glands, and lesions 

### typified as adenomatous 

### hyperplasia. 

### There is 

### conflicting evidence 

### whether 

### thyroid cancer is 

### increased in these 

### people 

### (55,56). In contrast to these observa

### tions, it seems 

### that domestic animals but not 

### wild animals in 

### iodide deficient areas 

### developed elevated 

### incidences of 

### thyroid tumors 

### (57), and tumor 

### incidence 

### disappeared in 

### dogs 

### following the advent of using 

### iodized salt 

### (58). Iodide may have

some 

### influence on 

### the 

### histological type 

### of 

### thyroid cancer, with follicular 

### being more
common in 

### iodidedeficient areas 

### and

### papillary being more common in 

### iodide rich

areas 

### (59). 

### People with various inborn

errors 

### ofmetabolism that are unable to syn

### thesize 

### enough 

### effective 

### thyroid hormone 

### develop very 

### enlarged 

### thyroids, but few

cases 

### of cancer 

### have 

### been 

### reported. There

are no 

### reports of 

### thyroid tumors 

### among persons 

### with resistance to 

### thyroid hormone 

### (60,61). In persons with 

### the autoimmune 

### disorder Graves' 

### disease, there are 

### often immunoglobulins that stimulate 

### thyroid cells in 

### ways 

### analogous to 

### TSH, even 

### though TSH 

### levels per se are very low. It is not known 

### whether there is an increase in 

### thyroid cancer among 

### these patients; some studies seem to indicate either that cancer incidence 

### may be increased or that 

### thyroid tumors in 

### these patients may 

### be more aggressive 

### (62,63). 

### Overall, this 

### qualitative information suggests 

### that 

### prolonged stimulation of the 

### human 

### thyroid under certain circumstances 

### may lead to 

### cancer, as in 

### the presence 

### of 

### inherited metabolic conditions

or 

### long-term immunologic 

### abnormalities, but there is 

### uncertainty in 

### this 

### conclusion. In 

### epidemiologic studies, goiter and 

### thyroidnodules have been shown to be risk factors for 

### thyroid cancer. The specific

causes ofthese enlargements are not known 

### but, where 

### studied, do not appear to be due to 

### hypothyroidism (64,65). Some researchers believe that part of the associationmaybedue to the 

### closemedical scrutinygiven to persons with 

### suspicious thyroid 

### enlargements 

### (66,67). In spite ofthe potential 

### qualitative sim

### ilarities, there is 

### evidence that humans may not be as 

### quantitatively sensitive to 

### thyroid

cancer

### development from 

### thyroid-pituitary

450 

### disruption as rodents. Rodents 

### readily respond to 

### reduced iodide intake with the 

### development of cancer; 

### humans 

### develop profound hyperplasia with 

### adenomatous 

### changes with 

### only suggestive evidence of 

### malignancy. Even with 

### congenital 

### goiters due to inherited blocks in 

### thyroidhormone 

### production, only a few 

### malignancies have been found in

### humans. The reasons for 

### differences in 

### perceived interspecies sensitivity are not fully known. However, one factor that mayplay a role in interspecies quantitative sensitivity to 

### thyroid stimulation deals with the influence ofprotein carriers ofthyroidhormone in theblood (Table 1). Both humans and rodents have nonspecific low 

### affinity protein carriers of 

### thyroid hormone (e.g., 

### albumin). However, in

### humans, otherprimates, and 

### dogs there is

a 

### high affinity 

### binding protein, 

### thyroxinebindingglobulin, whichbinds

### T4 (andT3 to

a lesser degree); this protein is missing in rodents and lower

### vertebrates. As a

### result, T4 bound to proteins with lower 

### affinity in the rodent is more 

### susceptible to removal from the 

### blood, 

### metabolism, and excretion 

### from the 

### body. In 

### keeping with this 

### finding, the

serum half-life ofT4 is much shorter in rats (<1 

### day) than in

### humans (5-9 

### days); thisdifference in T4 half-life results in a 

### 10-fold greater 

### requirement for 

### endogenous T4 in the rat thyroidthan in theadulthuman 

### (68). Serum T3 levels also show a species difference; the 

### half-life is 

### around 6 hr in rats and 24 hr in 

### humans 

### (69,70). There is a mor

### phological consequence to these hormone differences. High thyroid hormone synthetic activity is 

### demonstrated in 

### follicles in 

### rodents: theyare 

### relatively

### small, surrounded often

### bycuboidal epithelium. Follicles inprimates 

### demonstrate less activity and are large withabundant 

### colloid, and

### follicularcells are 

### relativelyflattened (lowcuboidal) (16). The 

### accelerated production of thyroid 

### hormone in 

### the rat is 

### driven by serum TSH 

### levels that are 

### probably about 6- to 60-fold 

### higher than in

### humans. This 

### assumes a

### basal TSH 

### level in rats and

### humans of200 

### ng/ml and 

### 5 

### pU/mI, respectively, and a 

### potency of 

### human TSH 

### of 

### 1.5-15 U/mg of

### hormone (71). Thus, itappears that the rodent thyroid glandis

### chronicallystimulatedbyTSH levels to 

### compensate for the increased 

### turnover of thyroid

### hormone. It follows 

### that increases in TSH levels above basal levels in rats could

more readily move the gland toward increased growth and potential 

### neoplastic change than in 

### humans. 

### Interestingly, adult male ratshavehigher serumTSH levels than females 

### (72, and they are often more sensitive to goitrogenic 

### stimulation and thyroid 

### carcinogenesis. In 

### humans, there is no 

### sex difference in hormone levels, but females

more 

### frequentlydevelop thyroidcancer (46). In addition to considerations about the influence of serum 

### thyroid hormone carrier 

### proteins, there are 

### differences between humans and animals in 

### size, 

### lifespan, basal metabolic rate, and 

### pharmacokinetics and 

### pharmacodynamics of 

### endogenous and
exogenous 

### chemicals. 

### Any comparison of 

### thyroid carcinogenic responses across 

### species shouldbe

### cognizant ofall these factors. The 

### guidance given here on 

### thyroid
tumors is not 

### unique. Other

### authorities have 

### recognized and 

### incorporated advances in the 

### understanding about 

### carcinogenic mechanisms into their assessments of cancer risks 

### (73-78). 

### Science 

## PolicyGuidance

Position Statements

Rodents andhumans share a common

### physiology in 

### regard to the 

### thyroid-pituitary feedback system. 

### Short-term

### perturbation in this system often leads to similar effects in both groups, 

### resulting in increases and 

### decreases in

### circulating

### thyroidand

### pituitary hormones. It is well 

### established in 

### rodents that 

### disruption of 

### thyroid-pituitary status with elevation of TSH levels is associated with 

### thyroid tumor and sometimes related 

### pituitary tumor 

### development. This is true whether it is due to 

### deficiency in 

### iodide, reduction in

### thyroidmass, presence of

### TSH

### producing pituitary tumors, or 

### administration ofgoitrogenic 

### chemicals. An increase in TSH stimulation of the 

### thyroid is a final

common 

### development. Likewise, administration of exogenous 

### thyroid hormone or removal of a TSH-increasing stimulus 

### reduces the

### effects in the 

### thyroid. The role of 

### thyroid-pituitary 

### disruption in cancer 

### development in 

### humans is much less convincing 

### than in animals. Iodide deficiency has been associated with increases in 

### thyroid cancer in some studies but not in

Table 1.Interspecies and intraspeciesdifferences

Parameter Human Rat Thyroxine binding Present Essentially globulin absent
T4half-life 5-9 Days 0.5-1 Day
T3 half-life 1 Day 0.25 Day
T4production rate/ 1x 10xthat in 

### kg

### bodyweight humans

SerumTSH 1x 6-60xthat in humans Follicularcell Low cuboidal Cuboidal 

### morphology

Sexdifferences SerumTSH M = F M<2xF Cancer sensitivity F = 2.5xM M > F

Abbreviations: T4, thyroxine; T3, triiodothyronine; TSH, thyroid stimulating hormone; M, male; F, female.

Volume 106, Number 8, August 1998 * Environmental Health PerspectivesReviews * Assessment of thyroid tumors

others. Similarlyanassociationbetweeneither inborn errors ofmetabolism 

### affecting thyroid hormone output or autoimmune-related Graves' disease and cancerhas been suggested but not 

### proven. TSH mayat least play some permissive role in carcinogenesis in humans. Accordingly, wecannot

### qualitativelyreject the 

### animal model; itseems 

### reasonable that itmay
serve as an 

### indicator of a 

### potential human 

### thyroidcancer

### hazard. However, to theextent 

### that humans are 

### susceptible to the tumorinducing 

### effects of 

### thyroid-pituitary disruption and

### given that 

### definitive human data are not 

### available, humans appear to be quantitativelyless sensitive than

### rodents to developing

cancer from perturbations in 

### thyroid-pituitary status. Recognizing these things and 

### based upon 

### thyroid carcinogenesis mode of action 

### considerations, the EPA 

### adopted the 

### followingthreescience

### policypositions:

1. It is

### presumed that

### chemicals that

### produce rodent 

### thyroid tumors may pose a carcinogenic

### hazard forthehuman

### thyroid. 2. In the absence 

### of

### chemical-specific data, humans 

### and rodents are 

### presumed to be 

### equally sensitive to 

### thyroid cancer due to 

### thyroid-pituitary 

### disruption. This is a conservative positionwhen 

### thyroid-pituitary disruption is the sole mode 

### of action in rats because 

### rodents appear to 

### be more sensitive to 

### this carcinogenic 

### mode ofaction 

### than 

### humans. When the 

### thyroid carcinogen is a

### mutagenic 

### chemi

### cal, the 

### possibility that children may 

### be

more sensitive 

### than 

### adults needs to 

### be evaluated on a

### case-by-casebasis. 3. Adverse 

### rodent noncancer 

### thyroid effects (e.g., 

### thyroid 

### gland enlargements) following short- and long-term reductions in 

### thyroid hormone levels are 

### presumed to pose

### human noncancerhealth

### hazards.

Some 

### chemicals that have 

### produced thyroid follicular cell tumors in 

### laboratory rodents appear to work 

### by

### producing a 

### dis

### turbance in 

### thyroid-pituitary 

### homeostasis, others appear to act 

### primarily 

### through a mutagenic 

### mode of action, 

### and still others

seem to show a 

### combination ofboth 

### modes

Table 2. Default dose-response procedures for thyroid carcinogens

Arrayofdata 

### DoseExample Antithyroid Mutagenic methodology

1 Unknown Unknown Linear 2 No Yes Linear 3 Yes No Nonlinear (MOE) 4 Yes Yes Linearand nonlinear (MOE)

MOE, margin of exposure. 

### of action. The question then becomes how to evaluate the risks of thyroid tumors for humans given exposure to any of these 

### chemicals. If the animal tumors are due to chemical doses that produce imbalances in thyroid-pituitary functioning, the chance of

cancer is 

### anticipated to be 

### minimal under conditions 

### of hormonal 

### homeostasis. Tumors 

### that seem to arise from relevant mutagenic 

### influences (e.g., gene mutations 

### and structural chromosome aberrations) 

### without perturbation in 

### thyroid-pituitary status maypose some chance ofcanceracross
a

### broaderrange

### ofdoses. 

### Consequently, 

### until such time 

### that

### biologicallybasedmodels and data become 

### available, the EPAhas adopted five other 

### science 

### policy positions for con

### ductingdose-response assessments ofchemi

### cal substances that have 

### produced thyroid 

### follicular cell 

### (and related pituitary) tumors inexperimental animals:

1. A

### linear dose-response procedure 

### should be 

### assumed when 

### needed experimental data to 

### understand the cause 

### of thyroid
tumors are 

### absent and the mode of action is unknown 

### (Table 2, 

### Example 1). 2. A linear dose-response procedure should 

### be assumed when the mode of action 

### underlying thyroid tumors is 

### judged to involve mutagenicity alone 

### (Table 2, 

### Example 2). 3. A 

### nonlinear 

### dose-response 

### relationship (margin

### ofexposure) 

### shouldbeusedwhen 

### thyroid-pituitary 

### disruption is 

### judged to 

### be 

### the solemode 

### ofaction 

### ofthe observed thyroid and related pituitary tumors 

### (Table 2, 

### Example 3). 

### Thyroid-pituitary perturbation is not 

### likely to have carcinogenic 

### potential in short-term or 

### highly infrequent exposure conditions. The margin 

### of exposure 

### procedure generally should be based on 

### thyroid-pituitary disruptive

### effects themselves, in

### lieuoftumor 

### effects, when data permit. 

### Such 

### analyses will aid in 

### the 

### development of combined

noncancer 

### and cancer assessments 

### oftoxicity. 

### Results 

### of the margin of exposure 

### procedure will be 

### presented in a way 

### that supports risk management 

### decisions for
exposure scenarios of

### differing types 

### (e.g., infrequent exposure, 

### short

### durations). 4. Consistent 

### with EPA risk 

### characterization

### principles, both linear andmargin 

### of
exposure considerations should be assumed when both 

### mutagenic and 

### thyroid-pituitary disruption modes ofaction

are 

### judged to be 

### potentially at work (Table 2, 

### Example 4). The 

### weight of evidence for 

### emphasizing one over the other should also be

### presented. The 

### applicability of each to different 

### exposure scenarios shouldbe

### developed for riskmanagement 

### consideration. 5. Dose-response relationships for neoplasms other than the thyroid (or pituitary) should be evaluated using mode of action 

### information bearing on their induction and principles laid out in current EPA cancer risk assessment guidelines. There is an association between 

### thyroidandliver tumors in 

### rodent cancer 

### studies (79,80). The reason(s) for this relationship has not been generically 

### established but should be carefully assessed 

### for 

### chemicals on a case-by-case 

### basis. Some may 

### be due to induction of hepaticmicrosomal enzymes.

Most of the focus in implementing this 

### policy is 

### devoted to 

### answering the following questions: 1) Does an agent that shows thyroid carcinogenic 

### effects have 

### antithyroid activity? 2) Can 

### modes of action 

### other than 

### thyroid-pituitary disruption account 

### for thyroid tumor 

### formation 

### by this 

### chemical? and 3) How can
one express 

### thyroid 

### dose-response 

### relationships? Adequately answering 

### these questions is 

### dependent upon a 

### data-rich 

### information base 

### for the chemical under review. To the extent 

### practicable, effort should be made to review 

### such information before 

### deciding upon the possible 

### mode of chemical action 

### underlying the 

### thyroid tumors 

### and their consequences 

### for 

### riskassessment. 

### The 

### procedures and considerations 

### developed in 

### this report 

### embody current 

### scientific knowledge of 

### thyroid carcinogenesis 

### and 

### evolving science 

### policy positions. 

### Should

### significant new 

### information become 

### available that would 

### change these positions, the EPAwill 

### update its science 

### policypositions 

### accordingly.


### Evidence for

### AntithyroidActivity

Data 

### needs. 

### Different types 

### of information

on a 

### chemical may 

### indicate that it 

### has 

### antithyroid activity, 

### that is, 

### whether it 

### works via 

### disruption 

### of 

### thyroid-pituitary
status. These 

### include 

### effects manifest in 

### the 

### thyroid 

### gland per se, various tissues 

### peripheral to 

### the 

### thyroid, and/or the liver. All 

### available factors are 

### assembled into an overall 

### evaluation 

### of the 

### likelihood that the 

### chemical is actingvia

### disruption ofthe 

### thyroid-pituitary axis. A 

### number of chemicals have been assessed (3). 

### Special mechanistic studies are needed to demonstrate 

### chemically induced perturbations in 

### thyroid-pituitary 

### functioning. Repeat dose (e.g., 2-4 week and 13 

### week) studies that have 

### simultaneously evaluated a number of end points can often 

### provide critical information for 

### evaluating 

### qualitatively whether 

### antithyroid activity exists, the cause of the activity, and 

### quantitatively

Environmental Health Perspectives * Volume 106, Number 8, August 1998 451Reviews * Hill et al.

what 

### dose-response 

### relationships may be 

### appropriate. Such studies should be carefully 

### designed to 

### encompass 

### multiple doses 

### from above those 

### clearly associated with tumors in chronic studies down to those below which there is no indication of dis

### turbance in critical 

### thyroid-pituitary para

### meters, so 

### that 

### dose-response 

### relationships

can 

### be defined. 

### Special attention 

### should be given to the time 

### of sampling of 

### thyroid andpituitary

### hormones because ofthe com

### pensatory action of homeostatic mechanisms and the 

### difficulty in 

### discerning changes after 

### compensation occurs. 

### Hormone sampling 

### should also be conducted at the same time 

### during the course 

### of a 

### day to minimize 

### circadian hormonal fluctuations, 

### and

### efforts shouldminimize stress in 

### handling animals. 

### Effects measured 

### only at 

### the 

### end ofchronic 

### rodent studies are 

### often 

### difficult to 

### evaluate 

### and, 

### alone, seldom

### provide

### adequate 

### information. The 

### determination of the 

### antithyroid activity of a chemical 

### requires 

### empirical demonstration of 

### the 

### following items. Demonstration 

### of increases in 

### thyroid growth and 

### changes in 

### relevant 

### thyroid and 

### pituitary hormones are 

### considered to 

### be the most important. Location 

### of the 

### site(s) of 

### antithyroid action 

### documents where in 

### the 

### body the chemical 

### under assessment 

### leads to 

### perturbations in 

### thyroid-pituitary functioning. Dose 

### correlations among various 

### effects determine where 

### the 

### growth curve 

### for the 

### thyroid gland deviates from the normal pattern 

### ofcell 

### replacement and how this 

### relates to doses 

### producing tumors. 

### Reversibility of 

### effects 

### following treatment cessation 

### during the 

### early stages of 

### disruption of the 

### thyroid-pituitary axis 

### shows that 

### permanent, 

### self-perpetuating processes 

### have not 

### been set 

### intomotion. 

### The 

### following three items are 

### desirable in 

### determining antithyroid activity: 

### lesion 

### progression, 

### structure-activity analysis, and other studies. 

### Each 

### provides supporting information that can 

### add

### profoundlyto 

### the assessment 

### of an 

### agent's 

### ability to 

### produce 

### antithyroid effects.
Increases in 

### cellular 

### growth (evidence required). Agents that affect 

### thyroid-pituitary function may stimulate 

### thyroid enlargement. Most parameters 

### commonly measured 

### include, but are not limited to, increases in absolute or 

### relative thyroid gland weight or 

### histological indications of cellular 

### hypertrophy and 

### hyperplasia, morphometric 

### documentation of 

### alteration in thyroid cellular 

### components, and 

### changes in the

### proliferation of

### follicular cells detected

### byDNA

### labeling ormitotic 

### indices. Hormone changes (evidence required). With a 

### disruption in 

### thyroid-pituitary func

### tioning, there is 

### typicallya 

### reduction in both 

### circulating serum 

### T4 and

### T3 concentrations and an increase inTSH 

### levelswithin

### days or
a few weeks of 

### chemical administration. In

some cases, 

### T4 levels may 

### be lowered 

### while T3 levels aremaintainedwithin normal limits. In 

### addition, sometimes hormone levels
may return to normal over time for 

### mild goitrogenic agents because ofthe 

### homeostatic compensatory increase in thyroid activity and mass. Statistical tests can 

### help evaluate the significance 

### ofhormone 

### perturbations, but it is the constellation of

### changes in both 

### thyroid andpituitaryhormones that 

### indicate whether the negative 

### feedback loop 

### between the 

### thyroid and 

### hypothalamus/pituitary has been

### perturbed. Site ofaction (evidence required). 

### Chemicals that produce thyroid tumors alone or after administration ofa mutagenic initiator 

### produce interference with thyroid-pituitary function at various sites in the

### body (Fig. 3). Effects have been found at

one or more of the 

### following anatomical 

### locations: intrathyroidal and various extrathyroidal sites, 

### induding the liver 

### and other sites. Clues to the site of action can sometimes be deduced 

### by 

### analysis of structurally related compounds. 

### Generally, enough information onachemical should

### be given to

### beable to 

### identifythesites 

### that con

### tribute the major effect on 

### thyroid-hypo

### thalamus-pituitary function. Given experience to 

### date, it appears that most often 

### the liveris the siteofaction, 

### followedbythethyroid, where 

### thyroid peroxidase is 

### affected; othersites ofaction seemto

### beless common. 

### Intrathyroidal. Several 

### different effects in the 

### thyroid gland have been associated with the 

### development of

### antithyroid activity and the 

### formation of 

### thyroid tumors in 

### rodents. Iodide pump 

### inhibition 

### by chemicals like 

### thiocyanate and 

### perchlorate ions 

### leads to a 

### decrease in 

### uptake 

### of inorganic iodide into 

### the thyroid gland. 

### Thyroid peroxidase inhibition blocks 

### the incorporation ofactive 

### iodide into 

### iodotyrosines and 

### their 

### coupling to form the nascent 

### thyroid hormones. 

### Agents that are 

### known to 

### reversibly

or

### irreversibly inactivate this enzyme 

### include various 

### thionamides such as 

### 6-propylthiouracil and 

### ethylene thiourea, certain aromatic 

### amines, e.g., some of 

### the 

### sulfon

### amides, and

### miscellaneous 

### compounds such

as 

### amitrole. 

### Toxicity to 

### thyroid cells, as has been seen with 

### polychlorinated 

### biphenyls,
mayaffect the

### gland'sabilitytomanufacture and secrete 

### thyroid hormones. Inhibition of 

### thyroid hormone 

### release, with agents like 

### lithium and excess 

### iodide, results in a retention of

### hormones within the colloid and a 

### paucityreleased into the

### circulation 

### (81). Extrathyroidal. Several tissues and
organs ofthe 

### body, including skeletal mus

### cle, 

### kidneys, and 

### liver, contain different 

### deiodinases that remove iodine atoms from 

### thyroid hormones. Inhibition of 5'-mon

### odeiodinase, the enzyme that

### normally converts

### T4 to

### T3, leads to a

### reduction in circu

### latingT3 and an increase in the rT3 

### levelvia 3 

### -deiodination. 

### Compounds like FD&C Red No. 3 

### (erythrosine), iopanoic 

### acid, and 

### 6-propylthiouracil act 

### by competitive inhi

### bition ofthis enzyme or interactionwith its 

### sulfhydryl cofactor. The 

### deiodinase system in 

### the 

### pituitary is 

### somewhat 

### different 

### from that in the 

### periphery and may

### respond dif

### ferentlyto certain

### chemicals 

### (82). A 

### significant amount of 

### thyroid hormone 

### normally is 

### metabolized 

### by the 

### liver. Certain 

### chemicals induce liver microsomal
enzymes and enhance 

### thyroid hormone metabolism and removal. T4 

### conjugation with 

### glucuronic acid is enhanced 

### by agents that 

### induce

### hepatic glucuronosyl transferase 

### (19). In these cases, 

### thyroid hormone may also show increased 

### binding to 

### hepatocytes, increased 

### biliary excretion, 

### and increased 

### plasma clearance. Other common 

### manifestations 

### of microsomal 

### induction include 

### enlargement of 

### hepatocytes in the centrolobular region, an increase in

### hepatic cell smooth 

### endoplasmic reticulum, an increase

Figure 3. Antithyroid effects that influence thyroid carcinogenesis. Abbreviations: TH, thyroid hormone; TSH, thyroid stimulating hormone.

Volume 106, Number 8, August 1998 * Environmental Health Perspectives 452Reviews * Assessment of thyroid tumors

in 

### P450-associated metabolism ofvarious 

### chemical substrates, and an increase in biliary

### flow. Disparate chemical and functional classes like 

### polyhalogenated hydrocarbons (e.g., 

### 2,3,7,8-tetrachlorodibenzo-p-dioxin), barbiturates (e.g., 

### phenobarbital), and various individual compounds (e.g., the pesticide 

### clofentezine, the drug 

### spironolactone, and thehistamine antagonist SK&F 934790) are known to 

### enhance thyroid hormone excretion via 

### effects on 

### microsomal enzymes. Conjugation also may occur with 

### sulfate, 

### usuallyassociated

### with deiodination; deamination, oxidative decarboxylation, and 

### ether-link 

### cleavage are minor 

### degradative pathways. 

### Interestingly, phenobarbital has been 

### shown to be a promoter in the 

### rodent 

### thyroid (35), but there is no 

### indication it 

### produces thyroidcancer inhumans (83). 

### Chemicals may bind 

### thyroid hormone receptors and 

### produce certain 

### effects. For instance, agents (e.g., 

### salicylates) can dis

### place 

### thyroid hormone from 

### plasma carrier 

### proteins and 

### result in reductions in

### effective thyroid hormone 

### (84,85). They could bind receptors in target organs (e.g., pituitary) 

### but result in inactive 

### complexes. These pos

### sibilities 

### plus other 

### potential sites 

### of action (e.g., 

### affecting TRH, 

### thyroid hormone responsive 

### elements on 

### the DNA) may 

### be 

### conceived as 

### influencing 

### thyroid-pituitary functioning.
Dose 

### correlations 

### (evidence required). Confidence in an 

### antithyroid mode of action is 

### enhanced

### byevidence ofa 

### correlation between 

### doses of a 

### chemical that do and do not 

### jointly 

### perturb thyroid-pituitary 

### hormone 

### levels, 

### produce various 

### his

### tological changes in 

### the 

### thyroid, or

### produce other 

### effects, including 

### thyroid cancer. These are important steps in 

### evaluating the 

### significance of

### thyroid-pituitary disruption in 

### thyroid carcinogenesis and in 

### evaluating dose-response 

### relationships. Reversibility 

### (evidence 

### required). Chemicals 

### working 

### through an 

### antithyroid mode of action induce 

### changes in 

### thyroid cell 

### morphology and 

### number and in 

### thyroid-pituitary hormones that are 

### reversible
upon cessation ofchemical 

### dosing. Lesionprogression 

### (evidence 

### desirable). Evidence for a 

### progression of

### histological lesions over time is 

### commonlynoted

### during the carcinogenic process. 

### These include cellular 

### hypertrophy and 

### hyperplasia, followed by focal 

### hyperplasia and, 

### eventually, 

### neoplasia 

### (benign and

### possiblymalignant tumors). Structure-activity 

### analyses 

### (evidence desirable). 

### Analysis of 

### chemical structure may show that an 

### agent 

### belongs to a class of

### compounds that induces 

### thyroid tumors via 

### thyroid-pituitary imbalance 

### (e.g., agents that inhibit 

### thyroid 

### peroxidase, liver 

### microsomal enzyme 

### inducers). This allows for 

### the 

### scientific inference that the 

### chemical 

### under reviewmayact 

### similarly. In 

### addition, generic 

### information developed on a group ofanalogues can be used to support the assessment ofthe agent under review. Other

### studies 

### (evidence

### desirable). Many other studies bearing on 

### thyroid-pituitary imbalance can provide a range of findings from strong 

### ancillary information to 

### only suggestive indications. For 

### example, a fewof these studies 

### indude suppression of induced 

### effects 

### by concurrent administration of 

### thyroid hormone; 

### absence of initiating 

### activity but presence 

### ofpromoting activity in twostage carcinogenicitytests; 

### localizationof

### certain chemicals in 

### the thyroid (e.g., 

### thionamides); influences on 

### hypothalamic responsiveness to 

### thyroid hormone levels 

### and output 

### ofTRH; 

### changes in TSH mRNA transcripts in 

### thepituitary; 

### andalteration 

### of

### thyroid 

### hormone nuclear receptor number or 

### synthesis.



### OtherModes 

### ofCarcinogenicAction
Another critical element in the evaluation of a 

### thyroid carcinogen is a 

### determination ofwhether mutagenicity may account 

### for the 

### observed tumors. Primary 

### emphasis should be 

### placed on those 

### end points that have mechanistic 

### relevance to carcinogenicity. DNA reactivity is a prime 

### predictor of 

### potential mutagenic carcinogenicity. Many 

### of these 

### compounds belong to 

### particular chemical classes (e.g., aromatic amines, nitrosamines, 

### polyaromatic hydrocarbons). These 

### chemicals or their 

### metabolites bind
to DNA, and 

### theyoften induce gene

### mutations 

### and 

### structural chromosome aberrations. In 

### recognition that organs 

### and tissues may

### have unique 

### metabolic activity, it is 

### helpful to know in 

### addition to 

### traditional short-term test 

### results 

### whether there is 

### evidence 

### ofDNAreactivity in target tissues 

### (e.g., DNA 

### adducts, unscheduled DNA 

### synthesis, single strand

### breaks). Mutagenic effects other than those 

### associated with 

### direct DNA reactivity 

### need
to 

### be 

### carefully evaluated in 

### regard to 

### their 

### mechanistic 

### implications; some may 

### have different cancer 

### dose-response considerations 

### than do direct DNA reactive agents. These 

### effects include the 

### ability of the 

### chemical under review to 

### induce indirect effects on DNA, such as 

### through influence

on the cell division 

### spindle or 

### production of reactive oxygen. Agents also should be evaluated for the 

### presence of structural alerts that are often 

### predictive of chemical reactivity or 

### potential carcinogenicity. All of these 

### findings are then melded into an overall 

### appraisal of an 

### agent's 

### ability to influence genetic processes relevant to carcinogenesis in the 

### thyroid or other sites. It is 

### possible that 

### information on carcinogenic 

### modes 

### ofaction other than muta

### genicity or 

### thyroid-pituitary derangement 

### will become available. Ifso, this information also needs to be incorporated on a case-bycase basis into 

### the evaluation ofa 

### chemical's 

### abilityto

### produce tumors ofthe thyroid (and 

### ofothersites).


### Dose-Response Considerations
Evaluation ofpotential 

### dose-response rela

### tionships 

### for thyroid tumors depends on an evaluation 

### ofthe chemical's expected mode 

### of carcinogenic 

### action. Major determinations include 

### whether the 

### thyroid tumors appear to 

### be 

### due, at least in part, to thyroid-pituitary imbalance andwhether other 

### modes of action (e.g., 

### relevant mutagenicity) may 

### be pertinent to 

### their formation. Other 

### case-specific factors may

### provide cru

### cial information, such as 

### the extent to 

### whichdatagaps 

### anduncertainties prevail. A 

### rationale should accompanythe selection of
any 

### dose-response method. Guidance is 

### providedbelowto 

### illustrateways to evaluate 

### data and make 

### judgments about 

### potential thyroidcancer

### dose-response relationships. 

### High to 

### low dose 

### extrapolation. If 

### antithyroidinfluences are

### operative in

### the

### formation 

### of thyroid tumors, attention should be directed to 

### biologically based procedures 

### that embody the mechanistic 

### influences, if 

### they are 

### available. In 

### their 

### absence, default procedures 

### shouldbe 

### employedthat incorporate

### nonlinear or

### linearconsiderations. When 

### thyroid-pituitary imbalance is not operative, 

### other modes of action or 

### default considerations 

### should be 

### used; 

### generally low-dose 

### linear 

### extrapolations are 

### appropriate. 

### All 

### extrapolation 

### procedures 

### should be consistent 

### with 

### the 

### guidance given in EPAcancer 

### riskassessment 

### guidelines. Finally, when 

### thyroid
tumors seem to arise 

### fromboth a 

### chemical's 

### antithyroid activity 

### and its 

### mutagenic 

### potential, 

### dose-response relationships may

### be pro

### jected inways 

### that express concerns 

### for both 

### possiblemodes 

### ofaction. 

### When tumors 

### other than 

### thyroid follicular cell 

### (and related 

### pituitary) tumors are 

### found 

### along with 

### thyroid tumors, 

### mode of action 

### and other 

### considerations should

### help guide the selection of the 

### appropriate 

### dose-response 

### extrapolation method(s). Separate 

### dose-response 

### extrapolations may 

### applyfor the

### different tumor types, 

### depending on the 

### specifics ofthe case. 

### Biologicallybased. 

### Optimally, mechanisticconsiderations thatunderlie

### thyroid tumor formation should be 

### incorporated into bio

### logically based 

### extrapolation models. 

### They should 

### indude

### physiologicallybased

### pharmacokinetic 

### considerations for the chemical and its interactions with and effects upon cells. The trouble is that 

### generic 

### biologicallybased

Environmental Health Perspectives * Volume 106, Number 8, August 1998 453Reviews * Hill et al.



### dose-response 

### extrapolation models haveyet to be developed and validated for the thyroid. 

### Fortunately, work in this area is 

### beginning, and a 

### model has been 

### developed to 

### explain effects associated with 2,3,7,8-tetra

### chlorodibeno-p-dioxin (86). Until other 

### mechanistic models 

### become 

### generally available and 

### chemical-specific data have been 

### produced, the EPAassessments will 

### employ,

as discussed

### below, one ofthree default pro

### cedures in its 

### evaluation of 

### thyroid cancer 

### risks: 

### nonlinear, 

### linear, or 

### both nonlinear 

### andlinear. Nonlinear. For cases in which tumors arise 

### from 

### chemically induced disturbances in 

### thyroid-pituitary 

### functioning, tumors are 

### considered to 

### be 

### secondary to 

### the adverse 

### effects on 

### thyroid 

### gland function that pre

### cede them. As exposures to 

### such agents 

### decrease, the likelihood of cancer 

### decreases; risks may 

### be seen as minimal at 

### doses at which 

### there is no 

### effect on 

### thyroid-pituitary homeostasis. 

### Generally, homeostasis is con

### sidered to 

### apply when serum 

### T4, 

### T3, and TSH levels and 

### thyroid and 

### pituitary mor

### phologyand

### growth are

### within their normal 

### limits. Risk assessments on agents 

### should contain 

### case-specific and generic 

### information 

### that support the contention 

### that nonlinear

### dose-response 

### relationships 

### apply. Empirically there is some 

### support for 

### thyroid follicular cell tumors 

### having a 

### dose-response curve 

### that is 

### less than linear (curvilinear 

### upward). 

### Slope functions were 

### calculated using 

### the Weibull model to give

some 

### indication of the 

### shape of the 

### dose-response curve 

### and the rodent tumor 

### incidence database of the National Cancer 

### Institute/National 

### Toxicology Program. 

### Incidence for tumors in 

### general was more consistent with a 

### quadratic rather than a linear 

### dose-response curve 

### shape (87,88). However, when 

### slopes for 

### thyroid follicular cell tumors were 

### compared with 

### those of 

### thyroid C cell tumors 

### and all 

### other tumor sites, those from the 

### thyroid follicular cells

were even more 

### curvilinear than the others 

### (Portier, personal communication). One argument 

### for assuming 

### low-dose 

### linearity in 

### dose-response assessments is 

### the concept of 

### additivity to 

### background. If a given chemical acts in the same wayor augments an 

### endogenous or exogenous background factor that 

### contributes to tumor 

### development, the effect ofthe chemical will add to that of the 

### background factor. The result is 

### low-dose linearity up to 

### at least a 

### doubling of the 

### background rate 

### (85). The 

### concept may not be 

### applicable to certain processes 

### subject to hormonal 

### regulation, such as with the thyroid gland. 

### Normally the level of circulating thyroid hormone is 

### adjusted carefully by 

### the negative feedback with thepituitary. Elevations and

### reductions in 

### thyroid hormone are met with 

### adjustments in 

### the amount 

### ofTSH 

### released from thepituitary so as to 

### bring thyroid

### hormone values back into the normal range. These excursions are not part of an 

### ongoing carcinogenic process; instead, 

### they represent the 

### body's means of maintaining 

### thyroid hormone 

### homeostasis. Small doses of a potentially antithyroid chemical may not result in anyperturbation in hormone 

### levels

or 

### stimulation of thyroid follicular cell growth simply because homeostatic mechanismswill drive 

### thyroidhormone levels 

### back into 

### thenormal range. The EPA 

### acknowledges that it may 

### be difficult to establish a precise dose where there is 

### negligible response fora

### specific tox

### icologic effect given the 

### sensitivity ofmethods to evaluate various parameters and the 

### variability in measurement ofendpoints. In recognition ofthis, it is 

### incumbent upon the scientific 

### community to help in the transfer ofvarious molecular 

### techniques from the research 

### laboratory to testing 

### facilities (e.g., measurement ofhormone receptor mRNA production and receptor content, occupancy, and turnover) thatmaybemore sensitive indicators 

### of

### thyroid-pituitarymalfunction. The way the EPAhas dealtwith nonlinear phenomena is to express concern 

### for human exposure 

### (risk) as a 

### margin ofexposure 

### (MOE), the ratio between a dose point of

### departure for the critical effect and the relevant estimate of 

### anticipated human exposure 

### (incorporating dose, 

### frequency, and time). Large MOEs are 

### attended with less

concern than are small ones. 

### Traditionally, the point of 

### departure is 

### expressed as a no observed adverse effect level 

### (NOAEL), and the critical effect is the relevant 

### toxicological end 

### point 

### occurring at the lowest doses in a 

### toxicological study. More 

### recently, alternatives to the NOAEL have 

### been proposed to

serve as points of

### departure for MOE calculation. In April 1996, the EPA proposed a revision 

### of its 

### existing cancer 

### risk 

### assessment 

### guidelines 

### (4. A dose point 

### of

### departure is 

### determined by extrapolating effects in the 

### observed part 

### of the 

### dose-response curve. It is 

### used, 

### depending on 

### the expected mode(s) ofaction, as the starting point for either linear 

### extrapolation to the 

### origin or 

### calculation ofan MOE in the case of

### nonlinear extrapolation. 

### Generally, tumor or 

### nontumor end point (e.g., 

### hyperplasia) incidence is 

### extrapolatedto the 

### 10% effectlevel. The 95% confidence levels are 

### placed on that 

### dose. The lower 95% confidence limit on that dose maybeusedas thepointof

### departure for

### risk estimation belowthe observed data. There is

some discussion about 

### using the 

### point estimate at the 10% effect level in lieu of the lowerbound estimate in the

### proposal. Other

means of 

### determining departure points are 

### also 

### proposed (2). Final cancer 

### guidelines will 

### darify these 

### points. Procedures should be 

### employed for 

### thyroid tumors 

### that are consistent with EPA cancer risk assessment 

### guidelines and

### practices that are

### applicable at the time. Assessments 

### should include 

### adequate information to aid in interpreting the 

### sig

### nificance of 

### MOEs, such as 

### taking into 

### consideration the 

### variability in 

### sensitivity
among 

### individuals within a 

### species, the 

### sensitivityofhumans relative to 

### experimental 

### animals, and other 

### strengths, weaknesses, and uncertainties 

### that are part of 

### the
assessment. Decision 

### makers must 

### then 

### judge the 

### adequacy of the MOE 

### for their riskmanagement purposes. 

### Low-dose linear. For 

### those assessment

cases in which 

### thyroid tumors do not seem to be due to 

### thyroid-pituitary imbalance 

### (e.g., mutagenic

### agents), existing

### case-specific 

### mode-of-action information and default 

### considerations should be used to 

### develop dose-response relationships. In 

### other cases, there may 

### be an 

### absence of

### mode-of-action information for an agent. 

### Generally a 

### lowdose 

### linear 

### default for the 

### thyroid tumors may be 

### contemplated in these two circumstances inaccordancewith current EPAprocedures. Recent cancer risk assessment 

### guideline proposals suggest that 

### linear 

### extrapolation would involve calculation ofa dose 

### point of

### departure with a 

### straight line 

### extrapolation fromthere to theorigin 

### (2). Low-dose linear and nonlinear. 

### Finally, careful review is warranted when both 

### antithyroid and 

### other 

### determinants seem to 

### applyto the

### observedthyroidtumors, suchas when there are certain mutagenic 

### influences (e.g., structural 

### chromosome 

### aberrations). 

### Judgments with accompanying scientific reasoning should be presented on the most appropriate 

### way(s) to 

### evaluate 

### thyroid risk: either linear or nonlinear or, when 

### the two 

### positions are about 

### equally tenable, both. When both 

### procedures are 

### presented, assessors 

### should state 

### the relative merits of 

### each 

### procedure. In some cases, one of 

### the two methods may be 

### preferable and 

### should 

### be given more weight; the rationale for 

### condusions shouldbeexpresslypresented. Projected risks using

### linear extrapolation often give rise to concerns at doses lower than those when nonlinear techniques are

### applied. Thus, these two techniques usuallycanbe seenasputting lowerandupperbounds onexposures ofconcern. Assessments should indude guidance for decision makers in interpreting concerns 

### for exposure when both extrapolation techniquesarepresented. Endpoints to be employed Optimally,

one would have access to data on various preneoplastic endpoints thatwouldbe evaluated 

### following short-term (e.g., 2-4 week)

Volume 106, Number 8, August 1998 * Environmental Health Perspectives 454Reviews * Assessment of thyroid tumors



### and subchronic (e.g., 13 week) studies and 

### comparedwith

### thedoses thathave

### produced
tumors in chronic studies. End points 

### that should regularly be evaluated and 

### presented in

### dose-response analyses include 1) changes in levels ofT4 and T3; 2) 

### increases in TSH; 3) the 

### incidence of 

### thyroid follicular cell hypertrophy, hyperplasia, and 

### neoplasia; 4) increases in 

### cell 

### proliferation and thyroid weight; and 5) 

### specific endpoints 

### associated with 

### thyroid-pituitary disturbance at the site(s) 

### ofchemical action (e.g., inhibition of 

### thyroid peroxidase, increased metabolism and clearance 

### of 

### thyroid hormone). A host 

### of other effects as 

### discussed above could be 

### monitored in 

### the 

### thyroid, pituitary, or 

### thyroid

### hormone-responsive organs and 

### included on a case-by-case basis. Care should be 

### taken to ensure 

### that 

### studies to 

### evaluate these 

### parameters are 

### conducted for 

### adequate periods 

### of time and at doses that clearly 

### define dose-response 

### relationships. Attention also needs to be given to procedures that help to reduce the variability in responses among animals (e.g., time 

### andmeans 

### ofanimal 

### sacrifice

### andtissue

### sampling). Estimation 

### ofpoints 

### ofdeparture. For 

### the important toxicity 

### studies, a 

### point 

### of 

### departure (e.g., 

### NOAEL) is determined 

### for 

### each 

### thyroid toxicity 

### end point and exposure

### duration. Doses 

### associatedwith tumors 

### should also be noted. The 

### departure point
may 

### be a 

### study dose or an 

### estimated dose. For instance, when data permit, the 

### departure point can be 

### estimated 

### by 

### extrapolation of doses 

### associated with 

### observed
responses (e.g., TSH levels) to those attended with no 

### significant deviation from the 

### control range. In other cases, an appropriate 

### observed 

### studyNOAEL may be selected or 

### other 

### procedures in 

### accordance with EPA 

### guidancemay

### be used. Considerations for the selection of the critical 

### end point to 

### be used to project 

### thyroidcancer

### risk (i.e., calculation ofthe

### MOE) include 1) the nature ofthe end

### point and its 

### relationship to the

### perturbations in

### endocrine balance and carcinogenicity; 

### 2) the presence 

### of 

### good dose-response or 

### dose-severity of 

### effect 

### relationships; 3) the sensitivity of the end

### pointvis-a-vis other

### potential end

### points; and 

### 4) the 

### length ofthe

### dosing

### periodand its 

### relevance to 

### making 

### judgments about the
consequences 

### of

### potential chronicexposures. 

### Interspecies 

### Extrapolation
Many considerations are relevant in attempting to 

### extrapolate 

### thyroid carcinogenic effects in 

### experimental animals to humans. The relative sensitivity of humans and rodents to the 

### carcinogenic effects of elevated TSH are not 

### firmly

### established, but important observations have been made. Given that the rodent is a sensitive model 

### formeasuring the 

### carcinogenic influences of TSH and that humans appear to be less 

### responsive, one would expect that projections 

### of potential risk for rodents 

### would

serve as 

### conservative potential indicators of risks forhumans. 

### Rodent cancer studies typically include doses that lead to 

### toxicity, 

### induding perturbation in 

### thyroid-pituitary functioning,

overalifetime. The relevance ofsuchexperi

### mental 

### conditions to 

### anticipated human
exposure scenarios (i.e., dose, 

### frequency, and time) 

### shouldbe considered andpresented in the 

### final 

### characterization of risk. This is 

### especially true because 

### thyroidal effects are not

### necessarilyexpectedatall doses. Inaddition, 

### chemically induced 

### effects that areproduced by short-term 

### disruption in 

### thy

### roid-pituitary functioning appear to be 

### reversiblewhen the stimulus is removed. Although it appears that

### humans are less sensitive to the 

### carcinogenic 

### perturbations of 

### thyroid-pituitary status than 

### rodents (e.g., iodide 

### deficiency), such 

### determinations should be 

### made on a 

### case-by-case basis. This would depend upon a host of 

### factors involving the agent, including 

### the 

### depth andbreadth 

### ofthe

### database, the con

### gruence 

### of the information supporting a given 

### mode of action, 

### and the existence 

### of information on 

### humans. Decision 

### makers should be 

### apprised ofrisk assessment judgments 

### and their 

### rationales. In 

### the absence of 

### chemical-specific information, the 

### default position is that humans should be considered to be as sensitive to 

### carcinogenic effects

as are rodents. That is to say, a 

### factorofone wouldbe usedwhen 

### extrapolating effects in rodents to those inhumans.
Human intraspecies 

### evaluations. 

### Thyroid hormones are 

### regulatedwithin 

### rather narrow ranges. 

### Normal human serum 

### values are as 

### follows: T4, 4-11 

### pg/dl and 

### T3, 80-180 

### ng/dl; TSH 

### levels extend over a 

### broader range: 0.4 to 8 

### pU/ml due to 

### the incorporation in recent 

### years ofmore sensitive laboratorymethods that have 

### extended the normal
range to lower values 

### (90,91). To the extent that data exist in humans as to their 

### thyroid-pituitary status, one 

### should 

### carefully review central value parameters between 

### chemically 

### exposed and 

### unexposed groups as 

### well as 

### the 

### distribution ofvalues between 

### bothgroups. Extended deviations in human 

### thyroid hormone levels either above or below the normal range are associated with the disease
states 

### hyperthyroidism and 

### hypothyroidism, respectively. In the United States, most cases

are associated with some autoimmune 

### problem. 

### Worldwide, iodide 

### deficiency is the mostprominent cause of

### thyroiddisease

### generally and 

### hypothyroidism 

### specifically. People 

### develop characteristic 

### symptoms and signs that readilycause them to seekmedical attention. 

### The goal 

### oftherapy for such con

### ditions is to 

### bring persons back into normal 

### thyroid-pituitary balance, which 

### secondarily would

### greatlyminimizeany

### potential forcarcinogenic effects. 

### Overt 

### hypothyroidism, with reduced 

### thyroidhormone and 

### increased TSH levels, requires 

### treatment; it has an incidence ofabout 0.2% in women and less in men. 

### Subclinical hypothyroidism may have an incidence of 5% among women. Men are 

### affected less 

### often; incidence increases 

### significantlywith age. There is not 

### agreement as to whether these people need treatment 

### (92). Some with 

### hypothyroidism
may go 

### for some time before diagnosis and treatment. 

### The possible 

### consequences of chemical exposure on this 

### subpopulation of 

### individualsmay

### warrant consideration. The human thyroid is 

### susceptible to ionizing radiation, the only known human 

### thyroid carcinogen. Children are more sensitive than adults to the carcinogenic effects 

### of ionizing 

### radiation (41,53). In keeping with the EPAposition on the evaluation of childhood risks (93), the impact of mutagenic chemicals that 

### produce thyroid
tumors 

### should be evaluated in context 

### of 

### the 

### information available on 

### the 

### subject as 

### well as 

### agent-specific information. The
extent to 

### which a 

### chemical may act as ionizing radiation does 

### should be evaluated on

a 

### case-by-case basis and 

### factored into 

### decisions 

### accordingly. It seems 

### possible that chemicals 

### producing mutagenic effects like those 

### of radiation may pose some accentuated risk to children. More research is needed in this area 

### (94). Combined

### effects. It is notknown ifthere

are 

### human 

### subpopulations that are sensitive
to 

### thyroid cancer 

### development from exposure to 

### antithyroidchemicals. 

### Seemingly, the 

### thyroid status ofpersons 

### living in an iodide

### deficient area or those who are 

### hypothyroid due to other causes may further 

### be harmed 

### bysimultaneous 

### exposure to 

### naturallyoccurring

### chemicals or

### xenobiotics that can 

### further 

### disrupt 

### thyroid-pituitary functioning (95). This 

### potential to

### possibly increase cancerrisk 

### following chemical 

### exposure should be 

### kept in mind in evaluating the composition of human

### populations, the numbers and nature 

### of sensitive 

### individuals, the 

### magnitude and pattern 

### of 

### chemical exposure, estimates 

### of risk to the 

### general 

### population, and the 

### potential risk 

### consequences to 

### persons with

some 

### increase in

### sensitivity.
In addition to 

### possible sensitive sub

### populations, persons may be 

### exposed to

more than one 

### antithyroid chemical at a time and by more than one route of exposure. These combined 

### exposures mayworsen 

### thyroid-pituitary status and influence 

### thyroid cancer 

### potential (96). To the

Environmental Health Perspectives * Volume 106, Number 8, August 1998 455Rviews's Hill et al.

extent practicable on a case-by-case basis, consideration 

### should be given to combined
exposures to chemicals that influence thyroid-pituitary 

### functioning. Attention can be 

### directed toward 

### 1) an 

### understanding of whether 

### the chemicals affect the same or different sites of antithyroid action, 2) whether mutagenicity or other modes of action may be operative, and 

### 3) the ways various 

### antithyroidal and other effects may combine to 

### influence potential cancer risks 

### by the same 

### and different routes of exposure. Some 

### guidance for 

### evaluating these

cases is 

### provided in the EPA mixtures assessment 

### guidelines 

### (94). Unlike tumors at many sites, 

### modes of action 

### for 

### thyroid follicular cell tumors can be 

### readily explored 

### through laboratory experimentation. By using this cancer 

### mode-of-action information 

### alongwith con

### siderations about intraspecies 

### and interespecies 

### variability, chemicals can be 

### assessed

as to 

### the consequences 

### ofhumanexposure.



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