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Hormonally Active Agents in the Environment (1999)

Chapter: 8 HAAs and Carcinogenesis in Animals

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Suggested Citation:"8 HAAs and Carcinogenesis in Animals." National Research Council. 1999. Hormonally Active Agents in the Environment. Washington, DC: The National Academies Press. doi: 10.17226/6029.
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8—
HAAs and Carcinogenesis in Animals

It has been hypothesized that environmental exposure to hormonally active agents (HAAs) results in an elevated risk of hormone-related cancers in humans. Human and experimental animal data link these cancers to exposure to endogenous hormones and diethylstilbestrol (DES) (see Appendix) (Herbst et al. 1971; Sonnenschein et al. 1974; Wiklund and Gorski 1982; Key and Pike 1988; Greenman et al. 1990; Brinton and Hoover 1993; Mittendorf 1995; Nandi et al. 1995). Endogenous estrogens have been associated with the development of tumors in the breast and endometrium in humans (Key and Pike 1988; Brinton and Hoover 1993; Nandi et al. 1995), and in the mammary, pituitary, and thyroid glands in animals (Sonnenschein et al. 1974; Wiklund and Gorski 1982; Greenman et al. 1990; Nandi et al. 1995). Endogenous estrogens could act as "initiators" by inducing DNA mutations (Liehr et al. 1986), as "promoters" by inducing cell proliferation (Russo and Russo 1978), or by allowing the persistence of tissues that normally regress or differentiate during development (Takasugi 1976: Bern 1992a). For a detailed discussion of the molecular mechanisms of estrogen-induced carcinogenesis, see Yager and Liehr (1996). The introduction of HAAs into the environment in the past 50-60 yr has preceded and overlapped the increasing incidence rates of some kinds of cancer. Because there is a lag period between exposure to a carcinogen and the induction of clinically apparent neoplasias, it is reasonable to investigate the association between HAAs and cancer.

This chapter reviews and evaluates data from animal studies relating environmental HAAs to cancers of the female and male reproductive systems and endocrine organs. The committee limited its review to cancer sites that are known from ancillary data to have some hormonal dependence and where activity should be most evident. However, the committee recognizes that some of the compounds discussed have been shown to cause cancer in other organ systems,continue

Suggested Citation:"8 HAAs and Carcinogenesis in Animals." National Research Council. 1999. Hormonally Active Agents in the Environment. Washington, DC: The National Academies Press. doi: 10.17226/6029.
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and in a variety of species. Compounds discussed in this chapter, with the exception of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), have been shown to possess estrogenic activity in at least one in vitro or in vivo bioassay (see Chapter 2). Finally, with the exception of DDT, it must be emphasized that this chapter focuses on postnatal exposures because no data are available on the carcinogenic effects of perinatal exposure to environmental HAAs to the F1 or succeeding generations.

Bioassays

Bioassays of the following compounds were evaluated with regard to carcinogenic effects in selected reproductive organs (i.e., endometrium/uterus, ovaries, testicles, and prostate gland) and endocrine organs (e.g., mammary, pituitary, thyroid, and adrenal glands): aldrin and dieldrin, 4,4'isopropylidenediphenol (bisphenol A), butyl benzyl phthalate (BBP), chlordecone, 1,1-dichloro-2,2-bis(p-chlorophenyl)ethane (DDD), 1,1- dichloro-2,2-bis(p-chlorophenyl)ethylene (DDE), dichlorodiphenyltrichloroethane (DDT), endosulfan, endrin, lindane, methoxychlor, polychlorinated biphenyls (PCBs), TCDD, and toxaphene. Table 8-1 presents the experimental details and the specific results of the bioassays. A summary of those findings is presented below, and is followed by a discussion of their strengths and limitations. Negative results should be interpreted to mean that the HAA did not cause tumor formation under the conditions tested. Different test conditions may yield different results in the incidence of tumors.

Aldrin and Dieldrin

Aldrin was tested in bioassays in B6C3F1 and C3HeB/Fe mice, Osborne-Mendel rats, and mongrel dogs (Davis and Fitzhugh 1962; Fitzhugh et al. 1964; NCI 1978e). Dieldrin was tested in C3HeB/Fe, CF1, or B6C3F1 mice (Davis and Fitzhugh 1962; Thorpe and Walker 1973; Walker et al. 1973; NCI 1978e) Fischer 344, Osborne-Mendel, and Carworth Farm "E" strain (CF "E") rats (Fitzhugh et al. 1964; Walker et al. 1969; NCI 1978 e,f); Syrian Golden hamsters (Cabral et al. 1979); and beagle and mongrel dogs (Fitzhugh et al. 1964; Walker et al. 1969). None of the bioassays involved perinatal exposure. Overall, there was no evidence that either aldrin or dieldrin induced tumors of the endometrium/uterus, ovaries, testicles, prostate gland, mammary gland, thyroid gland, pituitary gland, or adrenal glands.

Bisphenol A

Bisphenol A was tested for carcinogenicity in Fischer 344 rats and B6C3F1 mice (NTP 1982b). These tests involved exposure to adult animals only. An increase in testicular tumors (interstitial-cell tumors) was observed in 96% of thecontinue

Suggested Citation:"8 HAAs and Carcinogenesis in Animals." National Research Council. 1999. Hormonally Active Agents in the Environment. Washington, DC: The National Academies Press. doi: 10.17226/6029.
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rats of the low-dose group (p = 0.001) and in 94% of the high-dose group (p = 0.003), compared with 71% in the control group. However, the committee noted that aging Fischer 344 rats have a high incidence (more than 90%) of this type of tumor. Incidence data from the treated groups and the historical controls were not significantly different.

No increases were found in the incidence of tumors of the endometrium/ uterus, ovaries, prostate gland, mammary gland, thyroid gland, pituitary gland, or adrenal glands.

Butyl Benzyl Phthalate

Bioassays of BBP were conducted using Fischer 344/N rats (NTP 1997) and B6C3F1 mice (NTP 1982c). None of the studies involved prenatal exposure to BBP. There was no evidence that BBP increased the incidence of tumors of the endometrium/uterus, ovaries, testicles, prostate gland, mammary gland, thyroid gland, pituitary gland, or adrenal glands compared with controls.

Chlordecone

Chlordecone was tested in bioassays using Osborne-Mendel rats and B6C3F1 mice (NCI 1976). Tests were conducted only on adult animals. There was no evidence that chlordecone increased the incidence of tumors of the endometrium/ uterus, ovaries, testicles, prostate gland, mammary gland, thyroid gland, pituitary gland, or adrenal glands compared with controls. However, there is some evidence that chlordecone might induce cancers in the liver, which led the International Agency for Research on Cancer (IARC) to classify it as possibly carcinogenic to humans (IARC 1987).

DDD

DDD was evaluated for carcinogenicity in Osborne-Mendel rats and B6C3F1 mice (NCI 1978c). The tests involved exposure to adult animals only. DDD increased the incidence of thyroid tumors in male rats. The incidence of follicular-cell adenoma, follicular-cell carcinoma, c-cell adenoma, c-cell carcinoma, and adenoma was 50% in the low-dose group, 32% in the high-dose group, and 10% in control groups. The difference between the DDD-treated groups and the control groups was significant in the case of male rats with follicular-cell carcinoma and follicular-cell adenoma. There was no significant increase in the incidence of thyroid tumors in female rats. However, the authors indicate that the Cochran-Armitage test revealed a significant positive association between dose and combined incidence of follicular-cell adenomas and carcinomas in females. It is not known whether DDD induced the thyroid tumors through a hormonally mediated mechanism, although there is evidence that natural estrogens and DEScontinue

Suggested Citation:"8 HAAs and Carcinogenesis in Animals." National Research Council. 1999. Hormonally Active Agents in the Environment. Washington, DC: The National Academies Press. doi: 10.17226/6029.
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TABLE 8-1 Environmental HAAs and Cancer

Species (Reference)

Dose

Resultsa and Limitations

ALDRIN AND DIELDRIN

Rat

Osborne-Mendel

Aldrin. Males and females (50 per

Aldrin. No statistically significant increased incidence of tumors in reproductive or

(NCI 1978e)

group) received 30 or 60 ppm ( 1.5 or

other endocrine organs. There was a significant positive linear trend in the incidence

 

3.0 mg/kg/d) in diet for 74 (males) or

of follicular-cell adenoma or follicular-cell carcinoma of the thyroid in the male and

 

80 (females) wk.

female low-dose groups when compared with the pooled control group, but not when

   

compared with the matched control group. Both male and female high-dose groups

   

failed to confirm the significance seen in the low-dose groups. Additionally, cortical

   

adenomas of the adrenal gland were observed in females in significant proportions

   

(p = .001 ) in the low-dose group, but not in the high-dose group, when compared to

   

the pooled control group. These increased incidences were not consistently

   

significant when compared to matched rather than pooled control groups.

   

Males. Mammary fibrosarcoma: 2%, 0%, 0%; testicular: NTR; prostate: NTR:

   

pituitary chromophobe adenoma and chromophobe carcinoma: 35%, 33%, 33%;

   

thyroid follicular cell adenoma, follicular cell carcinoma, c-cell adenoma. and c-cell

   

carcinoma: 48%, 29%, 71%; adrenal cortical adenoma, cortical carcinoma,

   

pheochromocytoma: 6%, 5%, 20%.

   

Females. Uterine leiomyosarcoma and endometrial stomal polyp: 13%, 21%, 0%;

   

mammary papillary adenocarcinoma: 20%, 14%, 30%, ovarian oranulosa cell tumor:

   

2%, 9%, 0%; pituitary chromophobe adenoma: 35%, 23%, 44%; thyroid follicular

   

cell adenoma. follicular cell carcinoma, c-cell adenoma, and c-cell carcinoma: 41%,

   

37%, 22%: adrenal cortical adenoma: 18%, 2%, 0%.

Osborne-Mendel

Dieldrin. Males and females

Dieldrin. No statistically significant increased incidence of tumors in reproductive

(NCI 1978e)

(50 per group) received 29 or 65 ppm

or other endocrine organs. Females showed a significant (p = .007) difference

 

(1.45 or 3.25 kg/mg/d) in diet for 80

between combined incidence of adrenal cortical adenoma or carcinoma in the

 

(low-dose group) or 59 (high-dose

low-dose group and that in the pooled control group. However, the incidence in the

 

group) wk.

high-dose group was not significant, and the incidences were not significant when

   

matched controls were used for comparison. Males did not show a statistically

   

significant difference between treated and control groups.

   

(table continues)

Suggested Citation:"8 HAAs and Carcinogenesis in Animals." National Research Council. 1999. Hormonally Active Agents in the Environment. Washington, DC: The National Academies Press. doi: 10.17226/6029.
×

Page 214

TABLE 8-1 Continued

Species (Reference)

Dose

Results" and Limitations

   

Males. Mammary fibroma: 2%, 0%, 10%; testicular interstitial-cell tumor and

   

mesothelioma NOS: 4%, 0%, 0%; prostate: NTR; pituitary chromophobe adenoma,

   

chromophobe carcinoma, acidophil adenoma: 34%, 32%, 30%; thyroid follicular cell

   

adenoma, follicular cell carcinoma, c-cell adenoma, and c-cell carcinoma: 26%, 28%,

   

0%: adrenal cortical adenoma, pheochromocytoma, sarcoma NOS, ganglioneuroma:

   

2%, 11%, 10%.

   

Females. Uterine leiomyosarcoma and endometrial stromal polyp: 11%, 3%, 10%;

   

mammary adenoma NOS, adenocarcinoma NOS, fibroadenoma: 29%, 12%, 10%;

   

ovarian granulosa cell tumor: 4%, 2%, 0%; pituitary chromophobe adenoma,

   

chromophobe carcinoma: 27%, 27%, 50%; thyroid follicular cell adenoma, follicular

   

cell carcinoma, c-cell adenoma, and c-cell carcinoma: 37%, 34%, 25%; adrenal

   

cortical adenoma and carcinoma and pheochromocytoma: 13%, 8%, 0%.

Fischer 344

Dieldrin. Males and females (24 per

No statistically significant increased incidence of tumors in reproductive or other

(NCI 1978f)

group) received 2, 10, or 50 ppm

endocrine organs. This study is limited because too few animals were used and also

 

(0.1, 0.5, or 2.5 mg/kg/d) in diet for

the thyroids were not routinely examined microscopically.

 

104-105 wk.

 
   

Males. Mammary: NTR; testicular interstitial cell tumor: 96%, 100%, 83%, 100%:

   

prostate: NTR; pituitary adenoma: 13%, 41%, 4%, 0%; thyroid small cell carcinoma

   

and adenoma NOS: 0%, 0%, 100, 7%; adrenal gland: NTR.

   

Females. Uterine adenocarcinoma NOS, leiomyoma, endometrial stromal polyp,

   

endometrial stromal sarcoma: 80%, 63%, 46%, 59%; mammary adenoma, adeno-

   

carcinoma, cystadenoma, fibroma, fibroadenoma: 12%, 4%, 0%, 16%; ovary: NTR;

   

pituitary adenoma NOS: 30%, 17%, 9%, 8%; thyroid: NTR; adrenal gland: NTR.

Osborne-Mendel

Aldrin and Dieldrin. Males and

No significant increased incidence of tumors in reproductive or other endocrine

(Fitzhugh et al.

females (12 per group) received 0.5.

organs. This study is flawed because too few animals were used, the number of

1964)

2, 10, 50, 100, or 150 ppm (0.025,

animals examined microscopically was limited, and there were high levels of early

 

0.1, 0.5 2.5, 5, 7.5 mg/kg/d) in diet

mortality with insufficient numbers of animals surviving until termination of the

 

for 2 yr.

study.

(table continued on next page)break

Suggested Citation:"8 HAAs and Carcinogenesis in Animals." National Research Council. 1999. Hormonally Active Agents in the Environment. Washington, DC: The National Academies Press. doi: 10.17226/6029.
×

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(table continued from previous page)break

Species (Reference)

Dose

Resultsa and Limitations

Carworth Farm "E"

Dieldrin. Males and females (25

No significant increased incidence of tumors in reproductive or other endocrine

strain (Walker

per group) received 0.1, 1, or 10 ppm

organs. This study is flawed because the number of animals examined

et al. 1969)

(0.005, 0.05, or 0.5 mg/kg/d) in diet

microscopically was limited.

for 2 yr.

   

Mouse B6C3F1

Aldrin. Males (50 per group)

Aldrin. No statistically significant increased incidence of tumors in reproductive or

(NCI 1978e)

received 4 or 8 ppm (0.6 or 1.2

other endocrine organs.

 

kg/mg/d) in diet for 80 wk. Females

 
 

(50 per group) received 3 or 6 ppm

Males. Mammary: NTR; testicular interstitial cell tumor: 0%, 0%. 0%, 10%;

 

(0.45 or 0.9 kg/mg/d) in diet for

prostate: NTR; pituitary: NTR; thyroid follicular cell adenoma: 13%, 2%, 0%,0%;

 

80 wk.

adrenal gland: NTR.

 

Dieldrin. Males and females (50

Females. Uterine endometrial stromal polyp: 2%, 0%, 0%; mammary

 

per group) received 2.5 or 5 ppm

leiomysarcoma: 0%, 0%, 10%; ovarian leiomysarcoma: 0%, 0%, 10%; pituitary

 

(0.37 or 0.75 mg/kg/d) in diet for

chromophobe adenoma: 2%, 0%, 0%; thyroid adenoma: 2%, 0%, 0%; adrenal

 

80 wk.

leiomysarcoma: 0%, 0%, 10%.

   

Dieldrin. No statistically significant increased incidence of tumors in reproductive

   

or other endocrine organs.

   

Males. Mammary: NTR; testicular: NTR; prostate: NTR; pituitary: NTR; thyroid:

   

NTR; adrenal gland: NTR.

   

Females. Uterine endometrial stromal polyp: 0%, 2%, 0%, 0%; mammary: NTR;

   

ovary: NTR; pituitary chromophobe adenoma: 0%, 3%, 3%, 0%; thyroid follicular

   

cell adenoma: 0%, 0%, 0%, 10%; adrenal gland: NTR.

C3HeB/Fe

Aldrin and Dieldrin. Males and

No significantly increased incidence of tumors in reproductive or other endocrine

(Davis and

females (approximately 36 per group)

organs.

Fitzhugh 1962)

received 10 ppm (1.5 mg/kg/d) in

 
 

diet for 2 yr.

 

Carworth Farm

Dieldrin. Males and females (250-

No significantly increased incidence of tumors in reproductive or other endocrine

No. 1 (Walker et

400 per group) received 0.1, 1, or

organs.

al. 1973)

10 ppm (0.015, 0.15, 1.5 mg/kg/d)

 
 

in diet for 2 yr.

 
   

(table continues)

Suggested Citation:"8 HAAs and Carcinogenesis in Animals." National Research Council. 1999. Hormonally Active Agents in the Environment. Washington, DC: The National Academies Press. doi: 10.17226/6029.
×

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TABLE 8-1 Continued

   

Species (Reference)

Dose

Resultsa and Limitations

Carworth Farm

Dieldrin. Males and females (30

No significantly increased incidence of tumors in reproductive or other endocrine

No. 1 (Thorpe and

per group) received 10 ppm

organs.

Walker 1973)

1.5 mg/kg/d) in diet for 2 yr.

 

Hamster

Dieldrin. Males and females (36

No significantly increased incidence of tumors in reproductive or other endocrine

Syrian Golden

per group) received 20, 60, or 180

organs.

(Cabral et al. 1979)

ppm (0.8, 2.4, or 7.2 mg/kg/d) in diet

 
 

for life span.

 

Dog

Aldrin and dieldrin. Animals (sex

No significant increased incidence of tumors in reproductive or other endocrine

Mongrel

not specified. 26 total) received

organs. This study is flawed because too few animals were used and the length of

(Fitzhugh et al.

8-400 ppm (0.2-10 mg/kg/d) in diet

administration was not adequate for a carcinogenicity bioassay.

1964)

for up to 25 mo.

 

Beagle

Dieldrin. Males and females

No significant increased incidence of tumors in reproductive or other endocrine

(Walker et al. 1969)

(5 per group) received 0.1 or 1 ppm

organs. This study is flawed because too few animals were used and the length of

 

(0.005 or 0.05 mg/kg/d) in diet for

administration was not adequate for a carcinogenicity bioassay.

 

2 yr.

 

BISPHENOL, A

   

Rat

Males and females (50 per group)

No statistically significant increased incidence of tumors in reproductive or other

Fischer 344

received 1,000 or 2,000 ppm (50

endocrine organs. However, the incidence of mammary fibroadenomas in males was

(NTP 1982b)

mg/kg/d or 100 mg/kg/d) in diet for

increased in the high-dose group compared with the control group (8% in the high-

103 wk.

 

dose group: 0% in the control group). That is a statistically significant dose-response

   

trend based on the Cochran-Armitage test (p = .015).

   

Males. Mammary fibroadenoma: 0%, 8%, 0%; testicular interstitial-cell tumors:

   

96%. 94%, 71%; pituitary carcinoma and adenoma: 27%, 31%, 28%; thyroid C-cell

   

adenoma and C-cell carcinoma: 12%, 13%, 19%; adrenal-gland cortical adenoma,

   

cortical carcinoma, and pheochromocytoma: 14%, 15%, 31%.

(table continued on next page)break

Suggested Citation:"8 HAAs and Carcinogenesis in Animals." National Research Council. 1999. Hormonally Active Agents in the Environment. Washington, DC: The National Academies Press. doi: 10.17226/6029.
×

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(table continued from previous page)break

Species (Reference)

Dose

Resultsa and Limitations

   

Females. Mammary adenoma: 2%, 0%, 0%; ovarian granulosa-cell tumor and

   

fibrosarcoma: 2%, 0%, 4%; pituitary adenoma: 41%, 50%, 52%; thyroid C-cell

   

adenoma and C-cell carcinoma: 13%c, 11%, 8%; adrenal-gland neoplasm, cortical

   

adenoma, pheochromocytoma, ganglioneuroma: 18%, 16%, 30%.

Mouse

Males (50 per group) received 1,000

No statistically significantly increased incidence of tumors in reproductive or other

B6C3F1

or 5,000 ppm (150 mg/kg/d or 750

endocrine organs. However, the incidence of pituitary chromophobe carcinomas in

(NTP 1982b)

mg/kg/d) and females (50 per group)

males was increased in the high-dose group compared with the control group (7% in

 

received 5,000 or 10,000 ppm (750

the high-dose group; 0% in the control group). That is a statistically significant

 

mg/kg/d or 1,500 mg/kg/d) in diet

dose-response trend based on the Cochran-Armitage test (p = .016).

 

for 103 wk.

 
   

Males. Reproductive organs: NTR; pituitary chromophobe carcinoma: 0%, 7%, 0%;

   

adrenal cortical adenoma and sarcoma: 2%, 6%, 2%.

   

Females. Endometrial stromal polyp and leiomyosarcoma: 2%, 4%, 0%; mammary

   

adenocarcinoma and adenoma-squamous metaplasia: 2%, 2%, 0%; ovarian papillary

   

adenoma and granulosa-cell tumor: 0%, 4%, 0%; pituitary chromophobe adenoma and

   

chromophobe carcinoma: 0%, 3%, 5%; thyroid follicular-cell adenoma: 0%, 0%, 3%.

BUTYL BENZYL PHTHALATE

Rat

Males (60 per group) received 3,000.

No statistically significant increased incidence of tumors in reproductive or other

Fischer 344/N

6,000, or 12,000 ppm (120, 240, or

endocrine organs. Females exposed to the highest dose had an incidence of

(NTP 1997)

500 mg/kg/d) in diet for 2 yr.

fibroadenomas of the mammary gland that was statistically significantly decreased

 

Females (60 per group) received

compared to control animals (p = .001). This decreased incidence was attributed to

 

6,000, 12,000, or 24,000 ppm (300,

lower mean body weights in the dosed group.

 

600, 1200 mg/kg/d) in diet for 2 yr.

 
   

Males. Mammary carcinoma and fibroadenomas: 12%, 47% , 0%, 4%; testicular

   

adenocarcinoma (metastatic), interstitial cell adenoma: 92%, 98%, 90%, 88%;

   

prostate adenocarcinoma (metastatic): 0%, 2%,0%, 0%; pituitary adenoma and

   

carcinoma: 24%, 24%, 20%, 20%; thyroid c-cell adenoma, follicular cell adenoma,

   

follicular cell carcinoma: 8%, 6%, 8%, 10%; adrenal pheochromocytoma: 20%, 22%,

   

20%, 22%.

   

(table continues)

Suggested Citation:"8 HAAs and Carcinogenesis in Animals." National Research Council. 1999. Hormonally Active Agents in the Environment. Washington, DC: The National Academies Press. doi: 10.17226/6029.
×

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TABLE 8-1 Continued

   

Species (Reference)

Dose

Resultsa and Limitations

   

Females. Uterine deciduoma, leiomyoma, leiomyosarcoma, polyp stromal, sarcoma

   

stromal: 20%, 14%, 16%, 16%; mammary adenoma, carcinoma, and fibroadenomas:

   

62%, 66%, 22%, 65%; ovarian arrhenoblastoma NOS and granulosa cell tumor: 0%,

   

2%, 0%, 4%: pituitary adenoma and carcinoma: 52%, 52%. 26%, 45%; thyroid c-cell

   

adenoma, c-cell carcinoma, follicular cell adenoma, follicular cell carcinoma: 16%,

   

6%, 6%, 10%; adrenal ademona, carcinoma, ganglioneuroma, and

   

pheochromocytoma: 16%, 4%, 2%, 4%.

Mouse

Males and females (50 per group)

No statistically significant increased incidence of tumors in reproductive or other

B6C3F1

received 6,000 or 12,000 ppm (900

endocrine organs.

(NTP 1982c)

or 1,800 mg/kg/d) in diet for up to

 
 

103 wk.

Males. Mammary: NTR; testicles: NTR; prostate: NTR; pituitary: NTR: thyroid

   

follicular cell adenomas and follicular cell carcinoma: 2%, 0%, 4%.

   

Females. Uterine leiomyoma, leiomyosarcoma, endometrial stromal polyp, and

   

endometrial stromal sarcoma: 0%, 6%, 6%; mammary: NTR, ovarian:

   

cystadenocarcinoma NOS: 0%. 2%, 0%; pituitary adenoma NOS: 0%, 0%, 2%;

   

thyroid: NTR: adrenal cortical adenoma: 2%, 0%, 0%.

CHLORDECONE

 
   

Rat

Males (50 per group) received 8 or

No statistically significant increased incidence of tumors in reproductive or other

Osborne-Mendel

24 ppm (0.4 or 1.2 mg/k/d) in diet

endocrine organs.

(NCI 1976)

for 80 wk. Females (50 per group)

 
 

received 18 or 26 ppm (0.9 or 1.3

Males. Mammary fibroadenoma. adenoma, fibroma, adenocarcinoma, fibrolipoma:

 

mg/kg/d) in diet for 80 wk.

2%. 5%, 20%; testicular: NTR; prostate: NTR: pituitary chromophobe adenoma and

   

adenocarcinoma: 24%, 147%, 40%7; thyroid follicular cell carcinoma, follicular cell

   

adenoma, c-cell adenoma. c-cell carcinoma: 18%, 0%, 0%; adrenal cortical adenoma:

   

2%, 0%,0%.

   

Females. Uterine endometrial/stromal polyp, malignant lymphoma. squamous-cell

   

carcinoma: 8% , 4%; 0%; mammary fibroadenoma, adenoma, adenocarcinoma,

   

fibrolipoma: 14%, 4%, 50%; ovarian arrhenoblastoma and granulosa-cell tumor: 2%.

(table continued on next page)break

Suggested Citation:"8 HAAs and Carcinogenesis in Animals." National Research Council. 1999. Hormonally Active Agents in the Environment. Washington, DC: The National Academies Press. doi: 10.17226/6029.
×

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(table continued from previous page)break

Species (Reference)

Dose

Resultsa and Limitations

   

2%, 0%; pituitary chromophobe adenoma: 27%, 9%, 30%; thyroid follicular cell

   

carcinoma, follicular cell adenoma. c-cell adenoma, c-cell carcinoma: 6%, 7%, 0%;

   

adrenal cortical adenoma: 0%, 0%, 4%.

Mouse

Males (50 per group) received 20 or

No statistically significant increased incidence of tumors in reproductive or other

B6C3F1

23 ppm (3 or 3.45 mg/kg/d) in diet

endocrine organs.

(NCI 1976)

for 80 wk. Females (50 per group)

 
 

received 20 or 40 ppm (3 or 6

Males. Mammary: NTR; testicular: NTR; prostate: NTR; pituitary: NTR; thyroid:

 

mg/kg/d) in diet for 80 wk.

NTR; adrenal gland: NTR.

   

Females. Uterine/endometrial: NTR; mammary: NTR; ovarian cystadenoma: 0%.

   

2%, 0%; pituitary: NTR: thyroid: NTR; adrenal gland: NTR.

DDD

   

Rat

Males (50 per group) fed 1,647 ppm

Increased incidence of thyroid tumors in males; positive association between dose

Osborne-Mendel

or 3,294 ppm (82.3 mg/kg/d or 164.7

and combined incidence of thyroid tumors in females. The high incidence of tumors

(NCI 1978c)

mg/kg/d) in diet for 78 wk. Females

in control animals (37% mammary tumors, 21% pituitary tumors, 21% thyroid tumors

 

(50 per group) fed 850 ppm or

in females) raises concern about the interpretation of this study.

 

1,700 ppm (42.5 mg/kg/d or 85.0

 
 

mg/kg/d) in diet for 78 wk.

Males. Mammary fibroadenoma: 0%, 2%, 0%; testicle: NTR; prostate: NTR;

   

pituitary chromophobe adenoma and glioma: 27%, 24%, 5%; thyroid follicular-cell

   

adenoma, follicular-cell carcinoma, C-cell adenoma, C-cell carcinoma, and adenoma:

   

50%, 32%, 10%; adrenal-gland pheochromocytoma: 0%, 5%, 0%.

   

Females. Endometrial-uterine squamous-cell carcinoma: 3%. 3%, 0%; mammary

   

fibroadenoma and adenocarcinoma: 29%, 22%, 37%; ovary: NTR; pituitary

   

chromophobe adenoma: 47%, 36%. 21%; thyroid follicular-cell adenoma, follicular-

   

cell carcinoma, C-cell adenoma, and C-cell carcinoma: 31%, 22%, 21%; adrenal-

   

gland cortical adenoma, cortical carcinoma, and pheochromocytoma: 4%, 6%, 0%.

Mouse

Males and females (50 per group) fed

No statistically significant increased incidence of tumors in reproductive or other

B6C3F1

411 ppm or 822 ppm (61.6 mg/kg/d

endocrine organs.

(NCI 1978c)

or 123.3 mg/kg/d) in diet for 78 wk.

 
   

Males. Mammary: NTR; testicle: NTR; prostate: NTR; pituitary: NTR; thyroid:

   

NTR; adrenal gland: NTR.

   

(table continues)

Suggested Citation:"8 HAAs and Carcinogenesis in Animals." National Research Council. 1999. Hormonally Active Agents in the Environment. Washington, DC: The National Academies Press. doi: 10.17226/6029.
×

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TABLE 8-1 Continued

   

Species (Reference)

Dose

Resultsa and Limitations

   

Females. Endometrial stromal polyp: 3%, 0%, 0%; mammary: NTR; ovary: NTR;

   

pituitary: NTR; thyroid: NTR; adrenal gland: NTR.

DDE

   

Rat

Males (50 per group) fed 437 ppm or

No statistically significant increased incidence of tumors in reproductive or other

Osborne-Mendel

839 ppm (21.8 mg/kg/d or 42.0

endocrine organs. The high incidence of tumors in control animals (30% mammary

(NCI 1978c)

mg/kg/d) in diet for 78 wk. Females

tumors, 50% pituitary tumors, 15% thyroid tumors in females; 30% thyroid tumors in

 

(50 per group) fed 242 ppm or 462

males) raises concern about the interpretation of this study.

 

ppm (12.1 mg/kg/d or 23.1 mg/kg/d)

 
 

in diet for 78 wk.

Males. Mammary adenoma and fibroadenoma: 0%, 2%, 5%: testicular interstitial-

   

cell tumors: 0%, 6%, 0%; prostate sarcoma: 0%. 6%, 0%; pituitary carcinoma and

   

chromophobe adenoma: 22%. 5%, 0%; thyroid follicular-cell adenoma, follicular-cell

   

carcinoma, C-cell adenoma, and C-cell carcinoma: 30%, 23%, 30%; adrenal gland:

   

NTR.

   

Females. Endometrial-uterine sarcoma, leiomysarcoma, and stromal polyp: 9%. 8%,

   

0%; mammary adenoma. adenocarcinoma, and fibroadenoma: 24%. 16%, 30%;

   

ovarian cystadenoma: 3%, 0%, 0%: pituitary carcinoma and chromophobe adenoma:

   

30%, 52%, 50%; thyroid follicular-cell adenoma, follicular-cell carcinoma, C-cell

   

adenoma, and C-cell carcinoma: 35%, 29%, 15%; adrenal-gland cortical adenoma:

   

3%, 4%, 0% .

Mouse

Males and females (50 per group) fed

No statistically significant increased incidence of tumors in reproductive or other

B6C3F1

148 ppm or 261 ppm (22.2 mg/kg/d

endocrine organs.

(NCI 1978c)

or 39.1 mg/kg/d) in diet for 78 wk.

 
   

Males. Mammary: NTR; testicular interstitial-cell tumors: 2%, 0%, 0%; prostate:

   

NTR: pituitary: NTR; thyroid: NTR; adrenal gland; NTR.

   

Females. Endometrial-uterine adenocarcinoma, endometrial stromal polyp, and

   

hemanglioma: 0%, 4%, 6%; mammary adenocarcinoma and fibroadenocarcinoma: 4%,

   

0%, 5%, ovary: NTR pituitary: NTR, thyroid follicular cell carcinoma: 0%.

   

3%, 0%; adrenal gland: NTR.

(table continued on next page)break

Suggested Citation:"8 HAAs and Carcinogenesis in Animals." National Research Council. 1999. Hormonally Active Agents in the Environment. Washington, DC: The National Academies Press. doi: 10.17226/6029.
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Page 221

(table continued from previous page)break

Species (Reference)

Dose

Resultsa and Limitations

DDT

   

Rat

Males (50 per group) fed 321 ppm or

No statistically significant increased incidence of tumors in reproductive or other

Osborne-Mendel

642 ppm (16.0 mg/kg/d or 32.1

endocrine organs. However, a positive correlation between dose and incidence of

(NCI 1978c)

mg/kg/d) in diet for 78 wk. Females

pheochromocytoma in females was reported in this study. The high incidence of

 

(50 per group) fed 210 ppm or 420

tumors in control animals (40% mammary tumors, 68% pituitary adenoma, 26%

 

ppm (10.5 mg/kg/d or 21.0 mg/kg/d)

thyroid tumors in females; 16% pituitary tumors. 52% thyroid tumors in males) raises

 

in diet for 78 wk.

concern about the interpretation of this study.

   

Males. Mammary adenocarcinoma and fibroadenoma: 2%, 0%, 5%: testicle: NTR:

   

prostate: NTR; pituitary chromophobe adenoma: 18%, 14%, 16%: thyroid follicular-

   

cell adenoma, follicular-cell carcinoma, C-cell adenoma, and C-cell carcinoma: 55%,

   

51%, 52%; adrenal-gland pheochromocytoma: 4%, 0%, 0%.

   

Females. Endometrial stromal polyp: 5%, 13%, 0%; mammary adenoma,

   

adenocarcinoma. and fibroadenoma: 26%, 14%, 40%: ovary: NTR; pituitary

   

chromophobe adenoma: 41%, 48%, 68%; thyroid follicular-cell adenoma, follicular-

   

cell carcinoma, C-cell adenoma, and C-cell carcinoma: 37%, 26%, 26%; adrenal-

   

gland cortical adenoma and pheochromocytoma: 3%, 13%, 0%.

Osborne-Mendel

Males and females (24 per group)

No significant increased incidence of tumors in reproductive or other endocrine

(Fitzhugh and

fed 200-800 ppm (5.0-40.0 mg/kg/d)

organs.

Nelson 1947)

in diet for 2 yr.

 

Carworth

Males and females (40 per group) fed

No significant increased incidence of tumors in reproductive or other endocrine

(Treon and

2.5 ppm, 12.5 ppm, or 25 ppm

organs.

Cleveland 1955)

(0.12 mg/kg/d, 0.25 mg/kg/d, or 0.5

 
 

mg/kg/d) in diet for 2 yr.

 

Osborne-Mendel

Males and females (30 per group) fed

No significant increased incidence of tumors in reproductive or other endocrine

(Deichmann et al.

80 ppm or 200 ppm (4.0 mg/kg/d or

organs.

1967)

10.0 mg/kg/d) in diet for 2 yr.

 

Osborne-Mendel

Males and females (30 per group) fed

No significant increased incidence of tumors in reproductive or other endocrine

(Radomski et al.

80 ppm (4.0 mg/kg/d) in diet for 2 yr.

organs.

1965)

   
   

(table continues)

Suggested Citation:"8 HAAs and Carcinogenesis in Animals." National Research Council. 1999. Hormonally Active Agents in the Environment. Washington, DC: The National Academies Press. doi: 10.17226/6029.
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TABLE 8-1 Continued

   

Species (Reference)

Dose

Resultsa and Limitations

Mouse

Males (50 per group) fed 22 ppm or

No statistically significant increased incidence of tumors in reproductive or other

B6C3F1

44 ppm (3.3 mg/kg/d or 6.6 mg/kg/d)

endocrine organs.

(NCI 1978c)

in diet for 78 wk. Females (50 per

 
 

group) fed 87 ppm or 175 ppm (13.5

Males. Mammary: NTR; testicle: NTR; prostate: NTR; pituitary: NTR; thyroid

 

mg/kg/d or 26.2 mg/kg/d) in diet for

follicular cell adenoma: 0%, 2%, 0%; adrenal gland: NTR.

 

78 wk.

 
   

Females. Endometrial-uterine: NTR; mammary: NTR; ovary: NTR; pituitary

   

chromophobe adenoma: 7%, 0%, 5%; thyroid follicular-cell adenoma, follicular-cell

   

carcinoma, and C-cell adenoma: 5%, 8%, 0%; adrenal gland: NTR.

BALB/c

Males and females (28-30 per group)

No significant increased incidence of tumors in reproductive or other endocrine

(Tarján and

fed p,p'-DDT at 3 ppm (0.45

organs.

Kemény 1969)

mg/kg/d) in diet for 6 mo; 5-

 
 

generation study.

 

CF1

Males and females (60 per group) fed

No significant increased incidence of tumors in reproductive or other endocrine

(Turusov et al.

2 ppm, 10 ppm, 50 ppm, or 250 ppm

organs.

1973)

(0.3 mg/kg/d, 1.5 mg/kg/d, 7.5

 
 

mg/kg/d, or 37.5 mg/kg/d) in diet for

 
 

life span; 6-generation study.

 

BALB/c

Males and females (60 per group) fed

No significant increased incidence of tumors in reproductive or other endocrine

(Terracini et al.

2 ppm, 20 ppm, or 250 ppm (0.3

organs.

1973)

mg/kg/d, 3.0 mg/kg/d, or 37.5

 
 

mg/kg/d) in diet for life span;

 
 

2-generation study.

 

A strain

Males and females (total of 264

No significant increased incidence of tumors in reproductive or other endocrine

(Shabad et al. 1973)

animals) administered 50 ppm (7.5

organs. Early deaths occurred in the F0 F1, and F2 generations.

 

mg/kg/d) to F0 generation and 10

 
 

ppm (1.5 mg/kg/d) to F1-5 generations

 
 

by gavage for life span; 6-generation

 
 

study.

 

(table continued on next page)break

Suggested Citation:"8 HAAs and Carcinogenesis in Animals." National Research Council. 1999. Hormonally Active Agents in the Environment. Washington, DC: The National Academies Press. doi: 10.17226/6029.
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Page 223

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Species (Reference)

Dose

Resultsa and Limitations

CF1

Males and females (64 per group) fed

No significant increased incidence of tumors in reproductive or other endocrine

(Walker et al.

p,p'-DDT at 50 ppm or 100 ppm (7.5

organs.

1973)

mg/kg/d or 15.0 mg/kg/d) in diet for

 
 

2 yr.

 

CF1

   

(Thorpe and

Males and females (30 per group) fed

No significant increased incidence of tumors in reproductive or other endocrine

Walker 1973)

p,p'-DDT at 100 ppm (15.0 mg/kg/d)

organs.

 

in diet for 110 wk.

 

Hamster

Males and females (at least 40 per

Statistically significant increased incidence of adrenal-gland tumors in females.

(Rossi et al. 1983)

group) fed 1,000 ppm (40 mg/kg/d)

 
 

in diet for 30 mo.

 

(Cabral et al. 1982)

Males and females (29-40 per group)

Increased incidence (not statistically significant) of adrenal-gland tumors in males.

 

fed 1,000 ppm (40.0 mg/kg/d) in diet

 
 

for 28 mo.

 

(Agthe et al. 1970)

Males and females (30 per group) fed

No significant increased incidence of tumors in reproductive or other endocrine

 

500 ppm or 1,000 ppm (20.0 mg/kg/d

organs. Study is of limited value because of early deaths.

 

or 40.0 mg/kg/d) in diet for 48 wk.

 

(Graillot et al.

Males and females (15 per group) fed

No significant increased incidence of tumors in reproductive or other endocrine

1975)

250 mg/kg, 500 mg/kg, or 1,000

organs. Study is limited because length of administration was less than the life span.

 

mg/kg in diet for 18 mo.

 

Monkey

Animals (24) fed 400 ppm (20.0

No significant increased incidence of tumors in reproductive or other endocrine

(Adamson and

mg/kg/d) in diet for up to 10.8 yr.

organs.

Sieber 1983)

   

(Durham et al.

Animals (22) fed 5-5,000 ppm in diet

No significant increased incidence of tumors in reproductive or other endocrine

1963)

for up to 7 yr.

organs.

   

(table continues)

Suggested Citation:"8 HAAs and Carcinogenesis in Animals." National Research Council. 1999. Hormonally Active Agents in the Environment. Washington, DC: The National Academies Press. doi: 10.17226/6029.
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TABLE 8-1 Continued

   

Species (Reference)

Dose

Resultsa and Limitations

Dog

   

(Lehman 1965)

Males and females (22 total) fed

No significant increased incidence of tumors in reproductive or other endocrine

 

400-3,200 ppm (30.0-240.0

organs.

 

mg/kg/d) in diet for up to 4 yr.

 

ENDOSULFAN

   

Rat

Males (50 per group) fed 408 ppm or

No statistically significant increased incidence of tumors in reproductive or other

Osborne-Mendel

952 ppm (20.4 mg/kg/d or 47.6

endocrine organs in females.c The study is limited in that the dose was toxic to

(NCI 1978b)

mg/kg/d) in diet for 78 wk. Females

males. The high incidence of tumors in control animals (35% in mammary gland.

 

(50 per group) fed 223 ppm or 445

58% pituitary adenoma in females: 16% pituitary adenoma in males) raises concern

 

ppm ( 11.1 mg/kg/d or 22.2 mg/kg/d)

about the interpretation of this study.

 

in diet for 78 wk.

 
   

Males. Mammary fibroadenoma: 2%, 0%, 0%; testicle: NTR; prostate lipoma: 3%,

   

0%, 0%; pituitary chromophobe adenoma: 2%, 0%, 16%; thyroid follicular-cell

   

adenoma: 0%, 0%, 5%; adrenal gland: NTR.

   

Females. Endometrial-uterine lipoma, leiomyosarcoma, stromal polyp: 8%, 2%,

   

10%; mammary fibroadenoma and adenocarcinoma: 32%, 24%, 35%; ovarian

   

granulosa-cell tumors, lipoma, and leiomysarcoma (metastatic): 4%, 0%, 5%;

   

pituitary chromophobe adenoma: 33%, 19%, 58%; thyroid follicular-cell adenoma,

   

follicular-cell carcinoma, and C-cell adenoma: 2%, 4%, 11%; adrenal-gland cortical

   

adenoma: 4%, 0%, 0%.

Mouse

Males (50 per group) fed 3.5 ppm or

No statistically significant increased incidence of tumors in reproductive or other

B6C3F1

6.9 ppm (0.52 mg/kg/d or 1.0

endocrine organs in females. The study is of limited value because the dose was

(NCI 1978b)

mg/kg/d) in diet for 78 wk. Females

toxic to males.

 

(50 per group) fed 2.0 ppm or 3.9

 
 

ppm (0.3 mg/kg/d or 0.58 mg/kg/d)

Males. Mammary adenocarcinoma: 0%, 2%, 0%; testicle: NTR: prostate: NTR;

 

in diet for 78 wk.

pituitary: NTR: thyroid: NTR: adrenal gland: NTR.

(table continued on next page)break

Suggested Citation:"8 HAAs and Carcinogenesis in Animals." National Research Council. 1999. Hormonally Active Agents in the Environment. Washington, DC: The National Academies Press. doi: 10.17226/6029.
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Species (Reference)

Dose

Resultsa and Limitations

   

Females. Endometrial-uterine hemangiosarcoma: 0%, 2%, 5% (adenocarcinoma);

   

mammary adenocarcinoma: 2%, 2%, 0%; ovarian granulosa-cell tumors: 0%, 2%,

   

0%; pituitary chromophobe adenoma: 0%, 2%, 0%; thyroid: NTR, adrenal gland:

   

NTR.

ENDRIN

   

Rat

   

Osborne-Mendel

Males (50 per group) received 2.5 or

The Cochran-Armitage test for the incidence of adenomas of the pituitary in females

(NCI 1979b)

5 ppm (0.12 or 0.24 mg/kg/d) in diet

showed significance (p = .015) using the pooled controls, and the results of the

 

for 80 wk. Females (50 per group)

Fisher exact test showed that the incidence in the high dose group was statistically

 

received 3 or 6 ppm (0.15 or 0.3

significantly higher (p = .016) than that in pooled controls. There was a statistically

 

mg/kg/d) in diet for 80 wk.

significantly increased incidence of combined adenomas and carcinomas of the

   

adrenal gland in the low and high dose group males and in the low dose group

   

females. The incidence of these tumors in the matched controls of either sex were

   

higher than those of the corresponding pooled controls, and the incidences in the

   

matched controls equaled or exceeded those in any of the respective dosed groups.

   

NCI concluded that these tumors cannot be clearly related to administration of the

   

test chemcial.

   

Males. Mammary: NTR; testicles: NTR; prostate: NTR; pituitary adenoma NOS and

   

chromophobe adenoma: 31%, 31%, 40%; thyroid follicular cell adenoma, follicular

   

cell carcinoma, and c-cell adenoma: 9%. 7%, 11%; adrenal carcinoma NOS and

   

adenoma NOS: 8%, 18%, 22%.

   

Females. Uterine adenocarcinoma NOS. papillary adenoma, leiomyosarcoma,

   

endometrial stromal polyp: 14%, 4%, 26%; mammary adenoma NOS,

   

adenocarcinoma NOS, fibroma, fibroadenoma: 16%, 8%, 10%; ovarian fibroma 0%,

   

2%, 0%; pituitary carcinoma NOS, adenoma NOS, adenocarcinoma NOS,

   

chromophobe adenoma: 48%, 45%, 29%; thyroid follicular cell adenoma: 11%, 8%,

   

0%; adrenal carcinoma NOS, adenoma NOS, pheochromocytoma: 31%, 17%, 33%.

Osborne-Mendel

Males and females (50 per group)

No significant increased incidence of tumors in reproductive or other endocrine

(Deichmann et al.

received 2, 6, or 12 ppm (0.1, 0.3, or

organs. The study is limited in that not all tissues were examined microscopically.

1970)

0.6 mg/kg/d) in diet for 2.4 yr.

 
   

(table continues)

Suggested Citation:"8 HAAs and Carcinogenesis in Animals." National Research Council. 1999. Hormonally Active Agents in the Environment. Washington, DC: The National Academies Press. doi: 10.17226/6029.
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Page 226

TABLE 8-1 Continued

   

Species (Reference)

Dose

Resultsa and Limitations

Osborne-Mendel

Males and females (24 per group)

Carcinomas and sarcomas were present in the mammary gland and thyroid of both

(Reuber 1978a)

received 0.1-25 ppm (0.005-1.25

males and females. It is not stated whether the incidences of tumors were

 

mg/kg/d) in diet for 104 wk.

significant.

Mouse

Males (50 per group) received 1.6 or

No statistically significant increased incidence of tumors in reproductive or other

B6C3F1

3.2 ppm (0.24 or 0.48 mg/kg/d) in

endocrine organs. This study is limited in that survival of the low dose males could

(NCI 1979b)

diet for 80 wk. Females (50 per

not be evaluated, due to the accidental administration of excessive quantities of

 

group) received 2.5 or 5 ppm (0.37

endrin to this group during wk 66.

 

or 0.75 mg/kg/d) in diet for 80 wk.

 
   

Males. Mammary: NTR: testicular: NTR: prostate; NTR: pituitary: NTR; thyroid

   

NTR: adrenal gland: NTR.

   

Females. Uterine sarcoma NOS: 0%, 2%, 0%; mammary: NTR: ovarian

   

cystadenoma: 0%, 2%, 0%; pituitary: NTR: thyroid : NTR: adrenal gland: NTR.

LINDANE

   

Rat

Males (50 per group) fed 236 ppm or

No statistically significant increased incidence of tumors in reproductive or other

Osborne-Mendel

472 ppm (11.8 mg/kg/d or 23.6

endocrine organs.d The high incidence of tumors in control animals (50% in

(NCI 1977)

mg/kg/d) in diet for 80 wk. Females

mammary gland. 43% pituitary tumors in females; 34% follicular-cell carcinoma of

 

(50 per group) fed 135 ppm or 270

thyroid in males) raises concern about the interpretation of this study.

 

ppm (6.75 mg/kg/d or 13.5 mg/kg/d)

 
 

in diet for 80 wk

 
   

Males. Mammary carcinoma and adenoma: 2%, 4%, 0%; testicle: NTR: prostate:

   

NTR: pituitary carcinoma, adenoma. and chromophobe adenoma: 12%, 9%, 0%;

   

thyroid follicular-cell adenoma. follicular-cell carcinoma, and C-cell adenoma: 25%,

   

14%. 34%; adrenal-gland cortical adenoma: 0%, 3%, 0%.

   

Females. Endometrial-uterine adenocarcinoma, leiomyosarcoma, stromal polyp, and

   

carcinoma: 15%, 20%, 11%; mammary carcinoma, adenoma, adenocarcinoma,

   

fibroma, and fibroadenoma: 36%, 22%, 50%; ovarian sertoli-cell tumors: 0%, 2%,

(table continued on next page)break

Suggested Citation:"8 HAAs and Carcinogenesis in Animals." National Research Council. 1999. Hormonally Active Agents in the Environment. Washington, DC: The National Academies Press. doi: 10.17226/6029.
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Species (Reference)

Dose

Resultsa and Limitations

   

0%; pituitary carcinoma, adenoma, and chromophobe adenoma: 33%, 25%, 43%;

   

thyroid follicular-cell adenoma, follicular-cell carcinoma, and C-cell adenoma: 13%,

   

9%, 0%; adrenal-gland cortical adenoma: 7%, 5%, 0%.

Wistar (Ito et al.

Males (18-24 per group) fed 500 ppm

No significant increased incidence of tumors in reproductive or other endocrine

1975)

(25.0 mg/kg/d) in diet for 24-48 wk.

organs.

Wistar (Fitzhugh

Males and females (10 per group) fed

No significant increased incidence of tumors in reproductive or other endocrine

et al. 1950)

5-1600 ppm (0.25-80.0 mg/kg/d) in

organs.

 

diet for up to 107 wk.

 

Mouse

Males and females (50 per group) fed

No statistically significant increased incidence of tumors in reproductive or other

B6C3F1

80 ppm or 160 ppm (12.0 mg/kg/d or

endocrine organs.

(NCI 1977)

24.0 mg/kg/d) in diet for 80 wk.

 
   

Males. Mammary: NTR; testicle: NTR; prostate: NTR; pituitary: NTR; thyroid:

   

NTR; adrenal gland: NTR.

   

Females. Endometrial-uterine sarcoma: 0%, 2%, 0%,; mammary adenoma: 0%, 0%,

   

10%; ovary: NTR; pituitary: NTR; thyroid follicular-cell adenoma: 0%, 5%, 0%;

   

adrenal-gland cortical carcinoma: 2%, 0%, 0%.

dd

Males (20-40 per group) fed 455 ppm

No significant increased incidence of tumors in reproductive or other endocrine

(Ito et al. 1973)

(68.2 mg/kg/d) in diet for 24 wk.

organs.

dd

Males and females (10-11 per group)

No significant increased incidence of tumors in reproductive or other endocrine

(Hanada et al. 1973)

fed 546 ppm (81.9 mg/kg/d) in diet

organs. Dose might have exceeded maximum tolerated dose.

 

for 32 wk.

 

CF1

Males and females (30 per group) fed

No significant increased incidence of tumors in reproductive or other endocrine

(Thorpe and

400 ppm (60.0 mg/kg/d) in diet for

organs.

Walker 1973)

104 wk.

 

IRC-JCL

Males fed 600 ppm (90.0 mg/kg/d) in

No significant increased incidence of tumors in reproductive or other endocrine

(Goto et al.1972)

diet for 26 wk.

organs.

   

(table continues)

Suggested Citation:"8 HAAs and Carcinogenesis in Animals." National Research Council. 1999. Hormonally Active Agents in the Environment. Washington, DC: The National Academies Press. doi: 10.17226/6029.
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Page 228

TABLE 8-1 Continued

   

Species (Reference)

Dose

Resultsa and Limitations

NMRI

Males and females (50 per group) fed

No significant increased incidence of tumors in reproductive or other endocrine

(Herbst et al.1975)

12.5 ppm, 25 ppm, or 50 ppm (1.8

organs.

 

mg/kg/d, 3.7 mg/kg/d, or 7.5

 
 

mg/kg/d) in diet for 80 wk.

 

METHOXYCHLOR

   

Rat

Males (50 per group) fed 448 ppm or

No statistically significant increased incidence of tumors in reproductive or other

Osborne-Mendel

845 ppm (22.4 mg/kg/d or 42.2

endocrine organs.e The high incidence of tumors in control animals (45% in

(NCI 1978a)

mg/kg/d) in diet for 78 wk. Females

mammary gland, 40% pituitary adenoma in females: 17% in males) raises concern

 

(50 per group) fed 750 ppm or 1,385

about the interpretation of this study.

 

ppm (37.5 mg/kg/d or 69.2 mg/kg/d)

 
 

in diet for 78 wk.

Males. Mammary adenoma: 2%, 2%, 0%; testicular interstitial-cell tumors: 0%, 5%,

   

0%; prostate: NTRf; pituitary chromophobe adenoma: 38%, 18%, 17%; thyroid

   

follicular-cell adenoma, follicular-cell carcinoma, C-cell adenoma, and C-cell

   

carcinoma: 23%, 24%, 16%; adrenal-gland cortical adenoma and pheochromocytoma

   

6%, 5%, 5%.

   

Females. Endometrial stromal polyp: 3%, 11%,0%; mammary adenoma,

   

adenocarcinoma, and fibroadenoma: 34%, 28%, 45%; ovarian cystadenoma and

   

fibrosarcoma: 3%, 3%, 0%; pituitary chromophobe adenoma: 22%, 28%, 40%;

   

thyroid follicular-cell adenoma, C-cell adenoma, and C-cell carcinoma: 11%, 10%,

   

0%; adrenal gland: NTR.

Strain not specified

Males and females (25 per group) fed

No significant increased incidence of tumors in reproductive or other endocrine

(Hodge et al. 1952)

25-1.600 ppm (1.25-80 mg/kg/d) in

organs.

 

diet for 2 yr.

 

Osborne-Mendel

Males and females (30 per group) fed

No significant increased incidence of tumors in reproductive or other endocrine

(Radomski et al.

80 ppm (4 mg/kg/d) in diet for 2 yr.

organs

1965)

   

(table continued on next page)break

Suggested Citation:"8 HAAs and Carcinogenesis in Animals." National Research Council. 1999. Hormonally Active Agents in the Environment. Washington, DC: The National Academies Press. doi: 10.17226/6029.
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(table continued from previous page)continue

Species (Reference)

Dose

Resultsa and Limitations

Osborne-Mendel

Males and females (30 per group) fed

No significant increased incidence of tumors in reproductive or other endocrine

(Deichmann et al.

1,000 ppm (50 mg/kg/d) in diet for

organs.

1967)

27 mo.

 

Mouse

Males (50 per group) fed 1,746 ppm

No statistically significant increased incidence of tumors in reproductive or other

B6C3F1

or 3,491 ppm (262 mg/kg/d or 523

endocrine organs.

(NCI 1978a)

mg/kg/d) in diet for 78 wk. Females

 
 

(50 per group) fed 997 ppm or 1,994

Males. Mammary: NTR: testicle: NTR: prostate: NTR: pituitary: NTR: thyroid:

 

ppm (149.5 mg/kg/d or 299 mg/kg/d)

NTR; adrenal gland: NTR.

 

in diet for 78 wk.

 
   

Females. Endometrial stromal polyp: 0%, 8%, 5%; mammary: NTR; ovary

   

cystadenoma: 0%, 7%, 0%; pituitary: NTR; thyroid: NTR; adrenal-gland cortical

   

adenoma: 0%, 0%, 5%.

PCB

   

Rat

Males and females (24 per group) fed

No statistically significant increased incidence of tumors in reproductive or other

Fischer 344

Aroclor 1254 at 25 ppm, 50 ppm, or

endocrine organs. The high incidence of tumors in control animals (17% pituitary

(NCI 1978d)

100 ppm (1.25 mg/kg/d, 2.5 mg/kg/d,

adenoma in females, 100% interstitial-cell tumors in males), as well as the low

 

or 5.0 mg/kg/d) in diet for 104-105 wk.

number of animals in some groups, raises concern about the interpretation of this

   

study.

   

Males. Mammary: NTR; testicular interstitial-cell tumors: 100%, 83%, 83%, 100%;

   

prostate: NTR; pituitary adenoma (NOS): 8%, 0%, 0%, 0%; thyroid: NTR; adrenal-

   

gland pheochromocytoma: NTR.

   

Females. Endometrial-uterine adenocarcinoma, adenoma in adenomatous polyp,

   

leiomyoma, and stromal polyp: 58%, 33%, 84%, 14%; mammary adenoma and

   

adenocarcinoma: 17%, 0%, 0%, 4%; ovarian granulosa-cell tumors: 100% (1 animal),

   

0%, 0%, 0%; pituitary adenoma: 5%, 5%, 4%, 17%; thyroid: NTR; adrenal gland: NTR.

 

Sherman

Females (200 per group) fed Aroclor

No significant increased incidence of tumors in reproductive or other endocrine

(Kimbrough et al.

1260 at 100 ppm (5.0 mg/kg/d) in

organs.

1975)

diet for approximately 21 mo.

 
   

(table continues)

Suggested Citation:"8 HAAs and Carcinogenesis in Animals." National Research Council. 1999. Hormonally Active Agents in the Environment. Washington, DC: The National Academies Press. doi: 10.17226/6029.
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TABLE 8-1 Continued

   

Species (Reference)

Dose

Resultsa and Limitations

Sprague-Dawley

Males and females (70 per group) fed

No significant increased incidence of tumors in reproductive or other endocrine

(Norback and

approximately 70 ppm (3.5 mg/kg/d)

organs.

Weltman 1985)

Aroclor 1260 in diet for 24 mo.

 

Wistar

Males (141-152 per group) fed Clophen

No significant increased incidence of tumors in reproductive or other endocrine

(Schaeffer et al.

A-60 or Clophen A-30 at 100 ppm

organs.

1984)

(5.0 mg/kg/d) in diet for up to 28 mo.

 

TCDD

   

Rat

Males and females (50 per group) fed

No significant increased incidence of tumors in reproductive or other endocrine

Sprague-Dawley

0.02-2.0 ppb (0.001-0.1 mg/kg/d) in

organs. Significantly reduced incidence of tumors of the uterus, pituitary, mammary,

(Kociba et al. 1978)

diet for 2 yr.

and adrenal gland.

Osborne-Mendel

Males and females (50 per group)

In males, the incidence of follicular-cell adenoma in the thyroid was dose related and

(NTP 1982a)

received 0.2, 1.0, or 10.0 ppb (0.01,

significantly (p = .001) higher at the high dose than in controls. Increased incidence

 

0.05, or 0.5 µg/kg/wk) twice per wk

(not statistically significant) of thyroid tumors in females.

 

for 104 wk by gavage.

 
   

Males. Mammary adenoma, adenocarinoma, papillary adenoma, and fibroadenoma:

   

0%. 10%. 2%. 4%; testicular interstitial-cell tumors and lipoma: 0%, 4%, 0%, 0%;

   

pituitary adenoma (NOS) and chromophobe adenoma: 2%, 7%, 8%, 0%; thyroid

   

follicular-cell adenoma, follicular-cell carcinoma, C-cell adenoma, and C-cell

   

carcinoma: 14%, 26%, 30%, 0%; adrenal-gland pheochromocytoma and cortical

   

adenoma: 18%, 26%, 20%, 21%.

   

Females. Uterine squamous-cell carcinoma, adenocarcinoma. leiomyoma, and

   

leiomyosarcoma: 4%, 0%, 2%, 8%; mammary fibrosarcoma, lipoma, fibroadenoma,

   

and adenocarcinoma: 50%, 46%, 41%, 24%: ovarian thecoma, luteoma, and

(table continued on next page)break

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(table continued from previous page)continue

Species (Reference)

Dose

Resultsa and Limitations

   

granulosa-cell tumors: 2%, 0%, 6%, 0%; pituitary adenoma and chromophobe

   

adenoma: 11%, 5%, 9%, 14%; thyroid follicular-cell adenoma, C-cell adenoma, and

   

C-cell carcinoma: 10%, 18%, 26%, 17%; adrenal-gland adenoma, cortical adenoma,

   

cortical carcinoma, and pheochromocytoma: 18%, 10%, 30%, 21%.

Sprague-Dawley

Pregnant females (8 per group)

Females. Mammary adenocarcinomas in offspring after DMBA treatment: 90% and

(Brown et al. 1998)

received 1 pg/kg on d 15 post-

79%.

 

conception by gavage. Female

 
 

offspring received 30 mg DMBA/kg

 
 

at 50 d of age.

 

Mouse

Males (50 per group) received 0.0015,

In females, the incidence of follicular-cell adenoma in the thyroid was dose related

B6C3F1

0.0075, or 0.075 ppb (0.01, 0.05, or

and was significantly higher (p = .009) at the high dose than in controls.

(NTP 1982a)

0.5 µg/kg/wk) twice per wk for 104

 
 

wk by gavage. Females (50 per group)

Males. Reproductive organs: NTR; pituitary meningioma (invasive): 0%, 0%, 3%,

 

received 0.006, 0.03, or 0.3 ppb (0.01,

0%; adrenal heptocellular carcinoma (metastatic) and pheochromocytoma: 2%, 0%,

 

0.05, or 0.5 µg/kg/wk) twice per wk

0%, 4%; thyroid adenoma and follicular-cell adenoma: 6%, 0%, 0%, 5%.

 

for 104 wk by gavage.

 
   

Females. Mammary fibrosarcoma and fibroadenoma: 2%, 2%, 0%, 0%; uterine

   

fibroma, leiomyoma, carcinoma (NOS): 0%, 2%, 0%, 12%; ovarian papillary

   

adenoma, granulosa-cell tumor, and teratoma (benign): 4%, 2%, 2%, 0%; pituitary

   

adenoma (NOS) and chromophobe adenoma: 5%, 0%, 6%, 5%; adrenal cortical

   

adenoma and pheochromocytoma: 0%, 0%, 2%, 8%; thyroid adenoma (NOS) and

   

follicular-cell adenoma: 6%, 2%, 11%, 4%.

TOXAPHENE

   

Rat

Males (50 per group) fed 556 ppm or

In males the incidence of thyroid tumors was dose related (p = .007) using pooled

Osborne-Mendel

1,112 ppm (27.8 mg/kg/d or 55.6

controls. In females the incidence of thyroid tumors was dose related using either

(NCI 1979a)

mg/kg/d) in diet for 80 wk. Females

matched (p = .022) or pooled (p = .008) controls. The high incidence of tumors in

 

(50 per group) fed 540 ppm or 1,080

control animals (38% pituitary adenoma, 17% thyroid tumors in females; 43%

 

ppm (27.0 or 54.0 mg/kg/d) in diet

pituitary tumors, 14% thyroid tumors, 55% adrenal-gland tumors in males) raises

 

for 80 wk.

concern about the interpretation of study.

   

(table continues)

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TABLE 8-1 Continued

   

Species (Reference)

Dose

Resultsa and Limitations

   

Males. Mammary carcinoma: 2%, 0%, 0%; testicle: NTR; prostate sarcoma: 0%,

   

3%, 0%; pituitary carcinoma, adenoma. and chromophobe adenoma: 31%, 16%, 43%;

   

thyroid follicular-cell adenoma, follicular-cell carcinoma, C-cell adenoma, and C-cell

   

carcinoma: 21%, 26%, 14%; adrenal-gland adenoma, cortical adenoma, cortical

   

carcinoma, and pheochromocytoma: 12%. 11%, 55%.

   

Females. Endometrial-uterine carcinoma, papillary adenoma, and stromal polyp:

   

24%, 13%, 0%; mammary adenoma, adenocarcinoma, papillary adenocarcinoma,

   

fibroma, fibroadenoma, and teratoma (malignant): 28%, 32%, 10%; ovarian carinoma

   

and granulosa-cell tumors: 3%, 3%, 0%; pituitary adenoma, chromophobe adenoma,

   

and chromophobe carcinoma: 37%, 59%, 38%; thyroid follicular-cell adenoma and

   

C-cell carcinoma: 2%, 17%, 17%; adrenal-gland cortical adenoma and cortical

   

carcinoma: 7%, 14%, 0%.

Mouse

Males and females (50 per group) fed

No statistically significant increased incidence of tumors in reproductive or other

B6C3F1

99 ppm or 198 ppm (14.8 mg/kg/d or

endocrine organs.

(NCI 1979a)

29.7 mg/kg/d) in diet for 80 wk.

 
   

Males. Mammary: NTR: testicle: NTR; prostate: NTR; pituitary: NTR; thyroid:

   

NTR; adrenal gland: NTR.

   

Females. Endometrial-uterine leiomyoma, stromal polyp: 4%,0%, 0%: mammary

   

adenoma: 2%, 0%, 0%; ovary: NTR: pituitary: NTR: thyroid hyperplasia (follicular

   

cell): 0%, 3%, 0%; adrenal gland: NTR.

(table continued on next page)break

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(table continued from previous page)break

a Result values are shown in order of low-dose, mid-dose (if applicable), high-dose, and control groups.

b Reuber (1978b) reanalyzed the data and reported an increased incidence of pituitary tumors in low dose rats (27% for males; 27% for females) compared to

controls (0% for males; 4% for females).

c Reuber ( 1981 ) reanalyzed the data and concluded that the pooled incidence of all tumors of the female genital tract was increased (62%) compared to controls

(30%).

d Reuber (1979) reanalyzed the data and reported a significant increase in the incidence of ovarian tumors in the low-dose (45%) and high-dose (57%) groups

compared to controls (0%); a significant increase in pituitary tumors in the low-dose (37% in males; 59% in females) and high-dose groups (40% in males; 64 in

females) compared to pooled controls (16% in males; 21% in females); a significant increase in the incidence of thyroid tumors in males of the low-dose group

(42%) and in females of the low-dose (24%) and high-dose (28%) groups compared with pooled controls (18% for males; 7% for females); a significant increase

in the incidence of adrenal gland tumors (malignant and benign) in males and females of the low-dose (35% in males; 45% in females) and high-dose (60% in

males; 57 in females) groups compared to pooled controls (16% for males; 7% for females).

e Reuber (1980) reanalyzed the data and reported an increased incidence of mammary gland tumors in female rats in the low-dose (33%) and high-dose (30%)

groups compared to the control group (15%); a significant increase in the incidence of ovarian carcinomas in the low-dose (11%) and high-dose (23%) groups

compared to controls (0%); twice as many adenomas and carcinomas of the pituitary in female rats of the high-dose group (43%) compared to controls (20%); an

increased incidence of adrenal gland tumors in females of the low-dose (30%) and high-dose (38%) groups compared to controls (15%); an increase in thyroid

tumors in treated rats (no data were provided).

f NTR, no tumors reported.

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induce follicular-cell adenoma in mice (Greenman et al. 1990). However, male and female mice fed DDD did not develop thyroid tumors.

There was no evidence that DDD induced tumors of the endometrium/uterus, ovaries, testicles, prostate gland, mammary gland, pituitary gland, or adrenal glands.

DDE

DDE was tested for carcinogenicity in Osborne-Mendel rats and B6C3F1 mice (NCI 1978c). The tests involved exposure to adult animals only. There was no evidence in either species that DDE caused an increase in the incidence in tumors of the endometrium/uterus, ovaries, testicles, prostate gland, mammary gland, thyroid gland, or adrenal glands. An increased incidence of pituitary tumors was observed in rats of the low- and high-dose groups compared with control rats, but the effect was not dose related. It should be noted that 50% of the female controls had pituitary tumors, which is a higher incidence than normally observed in the historical controls. No pituitary tumors were observed in the study with mice.

DDT

DDT was tested in many bioassays in two strains of rat (Osborne-Mendel and Carworth) (Fitzhugh and Nelson 1947; Treon and Cleveland 1955; Radomski et al. 1965: Deichmann et al. 1967; NCI 1978c), four strains of mouse (B6C3F1, BALB/c, CF1, and A strain) (Tarján and Kemény 1969; Shabad et al. 1973; Terracini et al. 1973; Thorpe and Walker 1973; Turusov et al. 1973; Walker et al. 1973; NCI 1978c), hamsters (Agthe et al. 1970; Graillot et al. 1975; Cabral et al. 1982; Rossi et al. 1983), monkeys (Durham et al. 1963; Adamson and Sieber 1983), and dogs (Lehman 1965). Four of the studies with mice were multigeneration studies that involved exposure to DDT during fetal life, lactation, and after weaning for either 6 mo (Tarján and Kemény 1969) or for their life span (Shabad et al. 1973; Terracini et al. 1973; Turusov et al. 1973).

Two studies (Cabral et al. 1982; Rossi et al. 1983) reported an increased incidence of adrenal gland tumors (adrenocortical adenomas) in male and female hamsters. The increase was significant for the females. In two other studies with hamsters, DDT did not induce adrenal gland tumors, but early deaths occurred in one study (Agthe et al. 1970), and the length of administration was less than lifetime in the other (Graillot et al. 1975). In the bioassay conducted by NCI (1978c), DDT administration did not result in an increase in the incidence of adrenal gland tumors in rats or mice, but the Cochran-Armitage tests found a positive association between DDT and the incidence of pheochromocytoma in female rats. No increased incidence of adrenal gland tumors was observed in other bioassays with adult mice, rats, monkeys, or dogs or in multigeneration bioassays with mice exposed perinatally.break

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There was no evidence that DDT increased the incidence of tumors of the endometrium/uterus, ovaries, testicles, prostate gland, mammary gland, or pituitary gland in animals treated prenatally or in adulthood. However, there is some evidence that DDT might induce cancers in other organs, such as the liver, which led IARC to classify it as possibly carcinogenic to humans (IARC 1991).

A minor component of DDT—o,p'-DDT—is estrogenic at a dose of more than 25 mg/kg of body weight per day. That compound promoted the growth of MT2 mammary adenocarcinoma cells injected into ovariectomized Wistar-Furth rats (Robison et al. 1985b), which demonstrates that DDT can support the growth of an estrogen-responsive tumor.

Endosulfan

Endosulfan was tested in bioassays using Osborne-Mendel rats and B6C3F1 mice (NCI 1978b). The tests involved exposure to adult animals only. There was no evidence that endosulfan induced tumors of the endometrium/uterus, ovaries, testicles, prostate gland, mammary gland, thyroid gland, pituitary gland, or adrenal glands, but endosulfan was toxic to male rats and mice.

Endrin

Bioassays of endrin were conducted with Osborne-Mendel rats (Deichmann et al. 1970; Reuber 1978a; NCI 1979b) and B6C3F1 mice (NCI 1979b). All of these studies involved exposure to adult animals. One study (Reuber 1978a) reported an increased incidence of mammary gland and thyroid tumors in Osborne-Mendel rats, but two other bioassays in rats did not find an increase in those types of tumors (Deichmann et al. 1970; NCI 1979b). A bioassay with B6C3F1 mice (NCI 1979b) was also negative. Reuber's criteria for classifying tissues as tumorigenic were not consistent with those of other investigators (EPA 1979b).

There are data showing that endrin administered in the diet for up to 2 yr induced pituitary tumors in female but not in male Osborne-Mendel rats (NCI 1979b). The result for the Cochran-Armitage test for the incidence of adenomas of the pituitary in females was significant (p = .015) using the pooled controls, and the results of the Fisher exact test showed that the incidence in the high dose group was higher (p = .016) than that in the pooled controls. However, when the combined incidence of adenomas, carcinomas, adenocarcinomas, and chromophobe adenomas of the pituitary in female rats was compared with pooled controls, the results were not significant. In addition, two other studies did not report an increased incidence of pituitary tumors in Osborne-Mendel rats fed endrin for up to the 116 wk (Deichmann et al. 1970; Reuber 1978a). No pituitary tumors were reported in male or female B6C3F1 mice fed endrin for up to 2 yr (NCI 1979b).break

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There was no evidence that endrin increased the incidence of tumors of the endometrium/uterus, ovaries, testicles, or prostate gland compared with controls.

Lindane

Bioassays of lindane have been conducted in two strains of rat (Osborne-Mendel and Wistar) (Fitzhugh et al. 1950; Ito et al. 1975; NCI 1977) and five strains of mouse (B6C3F1, dd, CF1, IRC-JCL, and NMRI) (Goto et al. 1972: Hanada et al. 1973; Thorpe and Walker 1973; Herbst et al. 1975; NCI 1977). None of the studies involved prenatal exposure to lindane. Overall, there was no evidence that lindane increased the incidence of tumors of the endometrium/ uterus, ovaries, testicles, prostate gland, mammary gland, thyroid gland, pituitary gland, or adrenal glands compared with controls. However, there is some evidence that lindane might induce tumors of the liver, which led IARC (1987) to classify it as possibly carcinogenic to humans.

Methoxychlor

Bioassays of methoxychlor were conducted in Osborne-Mendel rats (Radomski et al. 1965; Deichmann et al. 1967; NCI 1978a), an unspecified species of rat (Hodge et al. 1952), and B6C3F1 mice (NCI 1978a). None of the studies involved prenatal exposure to methoxychlor. Overall, there was no evidence that methoxychlor increased the incidence of tumors of the endometrium/ uterus, ovaries, testicles, prostate gland, mammary gland, thyroid gland, pituitary gland, or adrenal glands compared with controls.

PCBs

Bioassays of PCBs have been conducted in four strains of rat (Fischer 344, Sherman, Sprague-Dawley, and Wistar) (Kimbrough et al. 1975; NCI 1978d; Schaeffer et al. 1984; Norback and Weltman 1985). None of these studies involved perinatal exposure to PCBs. There was no evidence in any of the studies that PCBs induced tumors of the endometrium/uterus, ovaries, testicles, prostate gland, mammary gland, thyroid gland, pituitary gland, or adrenal glands. However, there is some evidence that PCBs induce cancers of the liver, which led IARC to classify it as probably carcinogenic to humans (IARC 1987).

TCDD

TCDD has been evaluated for carcinogenicity in Sprague-Dawley rats (Kociba et al. 1978; Brown et al. 1998), Osborne-Mendel rats (NTP 1982a), and B6C3F1 mice (NTP 1982a). Of the reproductive and endocrine organs considered by thecontinue

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committee, an increased incidence of tumors from adult exposure to TCDD was observed only in the thyroid gland. There was an increase in the incidence of thyroid tumors in male and female Osborne-Mendel rats and in female B6C3F1 mice. The incidence of thyroid tumors was significantly increased (p = 0.001) in male rats and slightly increased in female rats administered 10 ppb TCDD by gavage twice a week for 2 yr (NTP 1982a). A significant increase (p = 0.009) in thyroid tumors was found in female, but not male, mice administered 0.3 ppb TCDD by gavage twice a week for 2 yr. However, there was no evidence that TCDD induced thyroid tumors in Sprague-Dawley rats fed up to 2 ppb TCDD in the diet for 2 yr (Kociba et al. 1978).

One study was conducted to investigate the effects of prenatal exposure to TCDD on chemically induced carcinogenesis (Brown et al. 1998). Eight pregnant rats were gavaged with 1 µg/kg TCDD on d 15 post-conception. Female offspring were subsequently treated with dimethylbenzanthracene (DMBA) at 50 d of age. Ninety percent of the animals developed mammary adenocarcinomas compared with 79% of control animals that were exposed to TCDD during gestation.

There was no evidence that adult exposure to TCDD caused tumors of the endometrium/uterus, ovaries, testicles, prostate gland, mammary gland, pituitary gland, or adrenal glands. In fact, a significant decrease in pituitary and adrenal gland tumors was observed in Sprague-Dawley rats (Kociba et al. 1978).

The committee restricted its evaluation of carcinogenicity to selected reproductive and endocrine organs, but TCDD has been shown to induce tumors in laboratory animals in other organs, including the liver, lungs, thymus, hard palate, nasal turbinates, and skin. IARC (1997) concluded there is sufficient evidence in experimental animals that TCDD is carcinogenic, and classified TCDD as a human carcinogen. Experimental evidence suggests that the carcinogenic effects of TCDD are mediated through the Ah receptor which is a nongenotoxic, epigenetic mechanism (Ahlborg et al. 1995).

Toxaphene

Toxaphene was tested in bioassays using Osborne-Mendel rats and B6C3F1 mice (NCI 1979a). The tests involved exposure to adult animals only. There was some evidence that toxaphene induced thyroid tumors in rats. In male rats, the incidence of thyroid follicular-cell adenoma or carcinoma was 17% in the low-dose group, 25% in the high-dose group, and 4.5% in the control group. This increase was dose related (p = 0.007) when compared with pooled control data. In female rats, the incidence of thyroid follicular-cell carcinoma was 2% in the low-dose group, 17% in the high-dose group, and 2% in the control group. This increase was dose related using either matched (p = 0.022) or pooled (p = 0.008) control data. It is not known whether toxaphene induced the thyroid tumors through a hormonally mediated mechanism, although there is evidence that natu-soft

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ral estrogens and DES induce follicular-cell adenoma in mice (Greenman et al. 1990). In the bioassay of toxaphene with mice, there was no evidence of an increased incidence of thyroid tumors.

There was no evidence that toxaphene induced tumors of the endometrium/ uterus, ovaries, testicles, prostate gland, mammary gland, pituitary gland, or adrenal glands. However, there is some evidence that toxaphene might induce cancers of the liver, as well as the thyroid gland, which led IARC to classify it as possibly carcinogenic to humans (IARC 1987).

Strengths and Limitations of the Cancer Bioassays

Several factors must be taken into consideration when interpreting the results of cancer bioassays. The factors include the genetic background of animals, the appropriateness of the animal model, the dose and route of administration, and the timing and duration of exposure during an animal's life span. In addition, the data themselves can be subject to different interpretations. The factors will influence the certainty expressed in conclusions drawn from the underlying data base.

Genetics

The genetic background of an animal strain can influence the results of a study. For example, when Fisher, Wistar-Furth, and Sprague-Dawley rats were administered the chemical carcinogens 7,12-dimethylbenzanthracene (DMBA) or nitroso-methylurea, more than 80% of the rats developed mammary tumors (Daniel and Joyce 1984; el Abed et al. 1987; Kort et al. 1987; Thompson et al. 1995; Russo and Russo 1996). Other rats, such as Copenhagen, had a significantly lower incidence of tumor development.

Different strains of rat and mice can also have varying incidences of spontaneous tumor formation that must be considered in the evaluation of carcinogenic agents. F344 rats are typically used in NCI bioassays because they have a low spontaneous incidence of mammary tumors, and B6C3F1 mice are used because they have a median incidence of liver tumors compared with other strains of mice (Eugene McConnell, Raleigh, N.C., personal commun., 1997). Many of the NCI bioassays reviewed used Osborne-Mendel rats, and no explanation was given for choosing this strain over F344 rats.

In cases where the spontaneous incidence of tumors in the control animals is high, detecting an increase in the frequency of tumor formation in treated animals would require larger sample sizes than typically found in animal bioassays, which normally employ 20-25 animals per group. For example, a high incidence of pituitary tumors was found in the control animals in studies of lindane (NCI 1977), methoxychlor (NCI 1978a), endosulfan (NCI 1978b), DDT (NCI 1978c), and DDE (NCI 1978c). Although the incidence of those tumors in experimental animals was not increased in comparison with the controls, the high incidence ofcontinue

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spontaneous pituitary tumors in the controls raises concern about the testing conditions.

In addition, it should be noted that tumor incidence can be altered by dietary modulation. For example, it has been shown that reducing calorie intake increases survival, decreases the incidence of spontaneous tumors, and might alter susceptibility to chemical carcinogens in laboratory animals (NRC 1996a). Thus. the sensitivity of rodent bioassays might be altered by the administered diet.

Animal Model

In the NCI bioassays, both rats and mice were typically tested because of the belief that a given event occurring in both species could be expected to occur in a third species (for example, humans) (Weisburger 1983). With the exception of PCBs, all the HAAs reviewed by the committee were tested in rats and mice; PCBs were tested in rats only. However, the bioassays described in this chapter may or may not have used the most susceptible species or strains of animals. For example, the spontaneous development of prostate cancer is a rare event in most nonhuman species. Only a few rat strains, such as Noble and Lobund-Wistar, have been used as models of prostate cancer. In those rat strains, androgens and estrogens increase the incidence of prostate cancer. The Noble rat appears to be uniquely sensitive to sex hormones for prostate cancer induction (Ofner et al. 1992). In this model, dysplasia in the dorsolateral lobe of rats treated with testosterone and estradiol is almost identical to the premalignant lesions described in the human gland (McNeal and Bostwick 1986). None of the studies on environmental HAAs described in this chapter were conducted using the Noble or Lorbund-Wistar strains. Also, there are no adequate animal models to test for endometrial or germinal-cell testicular cancers (which are the type of testicular tumor that is increasing in certain human populations).

Dose and Route of Administration

In NCI studies, animals are exposed via the most likely route of exposure in humans. Test animals are typically administered the maximum tolerated dose (MTD) and one-half of the MTD in cancer bioassays. The MTD is defined as the highest dose that does not alter the test animal's longevity or well-being because of noncancer effects (NRC 1993). Thus, the doses are not designed to be representative of environmental exposures. In the NCI (1978b) study on endosulfan, the sublethal doses administered to the male animals caused severe secondary effects and early death; therefore, carcinogenicity could not be assessed adequately. Because the highest dose used in a chronic toxicity study is based on the results from a prechronic toxicity study, the MTD is exceeded in some cases, as in the NCI endosulfan study. The other NCI and NTP studies discussed in this chapter showed no indication that the MTD was exceeded. However, there arecontinue

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concerns about the design of the typical long-term rodent bioassay, including the use of the MTD (see NRC 1993).

Timing and Duration of Exposure

The duration of exposure and period of observation must be considered when interpreting the results of a cancer bioassay. Experimental animals should be exposed to a range of doses of an agent for up to the life span of the animal to detect the effects of carcinogens with long latency periods and with multiple modes of action (for example, initiation or promotion). It is also important to take into account the stage in an animal's life cycle that exposure occurs. DES has been shown to cause cancer in humans and animals (Newbold 1995) when exposure occurs during critical periods of development but not when exposure occurs after the critical period. The timing of exposure during postnatal life also could affect carcinogenicity. In DMBA-induced mammary cancer in rats, a ''window of vulnerability" was identified between d 45 and 55 of life (Russo and Russo 1978); the administration of the carcinogen during that period significantly increased the incidence of carcinoma and decreased the latency period. The effect is explained by the induction of intense proliferative activity of structures called terminal end buds, from which new gland ducts originate during the period (Russo and Russo 1987).

Perinatal exposure was not addressed in the bioassays described in this chapter with the exception of several bioassays in which mice were exposed to DDT during fetal life, lactation, and after weaning by feeding or gavage for up to 6 mo or their life span. Those studies produced negative findings.

In a recent report, the U.S. Environmental Protection Agency's (EPA) FIFRA/Scientific Advisory Panel (SAP) reviewed an EPA analysis of combined perinatal and adult exposure, perinatal only exposure, and adult only exposure carcinogenesis bioassays to determine if the age of initial exposure to a chemical influences the carcinogenic response (EPA 1997). In the analysis, 69 carcinogenesis bioassays were reviewed. The studies analyzed included six NTP bioassays (Chhabra et al. 1992, 1993a,b), 13 unpublished FDA bioassays, and other studies previously reviewed by McConnell (1992). Chemicals tested in the bioassays reviewed by McConnell (1992) include three HAAs (dieldrin. DDT, and TCDD). The SAP agreed with the EPA's conclusion that perinatal exposure rarely identifies carcinogens that are not found in standard (adult only) carcinogenesis bioassays, and combined perinatal and adult exposure slightly increases the incidence of a given type of tumor. With respect to the latter, it is not known if this reflects the effect of an increased length of exposure, a heightened sensitivity of the young animal to the carcinogenic effects of the chemical, or variability in the experimental design or results.

EPA noted the available data for drawing conclusions are not very robust and has developed criteria for the inclusion of perinatal exposure into the standardcontinue

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carcinogenesis bioassay. The criteria include factors such as the likelihood of widespread exposure to women of childbearing age, infants and children, and specific toxicity to the developing fetus. A weight-of-the-evidence approach is applied to these factors to determine if a chemical is a candidate for perinatal carcinogenesis testing. The Food and Drug Administration (FDA) (1982) has also developed a set of criteria for determining candidates for perinatal carcinogenesis bioassays that are based on use, exposure, and toxicity seen in developmental toxicity and reproductive studies.

Other Interpretations

One investigator has published different interpretations of some of the NCI and FDA studies described in this chapter (see Table 8- 1 footnotes b, c, d, and e). Reuber (1978b, 1979, 1980, 1981) reported positive results in reanalyses of NCI (1976, 1977, 1978a,b) studies and unpublished FDA studies, all of which reported negative results. Reuber concluded that methoxychlor increased the incidence of mammary, ovarian, testicular, pituitary, thyroid, and adrenal gland tumors, that endosulfan increased the incidence of all tumors of the female genital tract, and lindane increased the incidence of ovarian, pituitary, thyroid and adrenal gland tumors, and that chlordecone increased the incidence of pituitary tumors. Because Reuber (1978b, 1979, 1980, 1981) did not indicate why he considered the original NCI (1976, 1977, 1978a,b) interpretation of the tissues questionable or how the tissues were reexamined, his reanalysis cannot be independently verified.

Summary and Conclusions

Given that there are data from animal and human studies that indicate endogenous estrogens play some role in increasing the incidence of tumors in various endocrine glands in humans (Key and Pike 1988; Brinton and Hoover 1993; Nandi et al. 1995), and animals (Sonnenschein et al. 1974; Wiklund and Gorski 1982; Greenman et al. 1990; Nandi et al. 1995) and that the introduction of HAAs into the environment has preceded and overlapped the increasing incidence rates of some types of cancer, an association between HAAs and cancer is a reasonable hypothesis. Animal bioassays have been conducted to assess the carcinogenicity of aldrin and dieldrin, bisphenol A, BBP, chlordecone, DDD, DDE, DDT, endosulfan, endrin, lindane, methoxychlor, PCBs, TCDD, and toxaphene. Overall, the available animal data do not support an association between environmental HAAs and cancers of the female and male reproductive systems and endocrine organs. However, some of the HAAs evaluated have been shown to induce tumors in other organs. IARC has classified lindane, toxaphene, p,p'-DDT, and chlordecone as possibly carcinogenic, PCBs as probably carcinogenic, and TCDD as carcinogenic in humans.break

Suggested Citation:"8 HAAs and Carcinogenesis in Animals." National Research Council. 1999. Hormonally Active Agents in the Environment. Washington, DC: The National Academies Press. doi: 10.17226/6029.
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The few human studies that are available are in general agreement with the animal studies described in this chapter. Human studies conducted to date do not find an association between breast, endometrial, or testicular cancers and DDT. DDE, PCBs, or TCDD (see Chapter 9). However, several of these studies are limited by factors such as small case numbers and lack of exposure measurements in body fluids and tissues. Based on the available data, animal studies have also not found an association between DDT, DDE, PCBs, or TCDD and breast, endometrial, or testicular tumors.

Liver cancer in wild fish populations has been conclusively linked to the presence of known carcinogens, especially polynuclear aromatic hydrocarbons (PAHs), in the environment (Harshbarger and Clark 1990; Baumann and Harshbarger 1995). The liver is an estrogen-responsive organ in fish, and laboratory experiments in two-stage models of carcinogenesis in two species have indicated that estradiol is a tumor promoter in some fish (Nunez et al. 1989; Cooke and Hinton 1999). It is possible that environmental estrogens act in this way in wild fish, but it has not been confirmed. Tumors in endocrine organs of fish occur in regions contaminated with pesticides: but it is not known whether those chemicals are the causative agents (Harshbarger and Clark 1990).

Body burdens of PCBs, DDT, and DDE have been decreasing over the past 30 yr largely due to regulatory intervention. However, the body burden and exposure to the majority of environmental HAAs, including other estrogenic pesticides, antioxidants, and plasticizers is not known, and the potential cumulative effects of environmental HAAs is yet to be fully explored. In addition, not all HAAs have yet been tested for carcinogenicity, including some phthalates and alkyl phenols. The large number of studies reviewed by the committee that examined the carcinogenicity of some of the most studied HAAs in many species under a great variety of experimental circumstances failed to adduce compelling evidence that HAAs induce cancers of the female and male reproductive systems and other endocrine organs. However, most of the available studies involved high-dose, postnatal testing. Little or no data are available on whether prenatal exposure to HAAs can cause cancers of the endocrine system.

Recommendations

Because perinatal exposure for the most part has not been addressed with respect to carcinogenesis, research in laboratory animals is needed on the role of prenatal exposure to suspected chemicals in inducing cancers later in life or in subsequent generations. Initial studies should focus on HAAs that have been shown to induce cancer of the thyroid, pituitary, and adrenal glands in some laboratory animals.break

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Some investigators have hypothesized that estrogens and other hormonally active agents found in the environment might be involved in breast cancer increases and sperm count declines in humans as well as deformities and reproductive problems seen in wildlife.

This book looks in detail at the science behind the ominous prospect of "estrogen mimics" threatening health and well-being, from the level of ecosystems and populations to individual people and animals. The committee identifies research needs and offers specific recommendations to decision-makers.

This authoritative volume:

  • Critically evaluates the literature on hormonally active agents in the environment and identifies known and suspected toxicologic mechanisms and effects of fish, wildlife, and humans.
  • Examines whether and how exposure to hormonally active agents occurs—in diet, in pharmaceuticals, from industrial releases into the environment—and why the debate centers on estrogens.
  • Identifies significant uncertainties, limitations of knowledge, and weaknesses in the scientific literature.

The book presents a wealth of information and investigates a wide range of examples across the spectrum of life that might be related to these agents.

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