Xenobio’c)induced,Rodent Tumors,of,Ques’onable ... · Relevance,...

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Xenobio'c-‐induced Rodent Tumors of Ques'onable

Relevance to Human Cancer Risk

R. R. Maronpot Maronpot@me.com

Photomicrographs courtesy of the National Toxicology Program (http://ntp.niehs.nih.gov)

Rodent Tumors of Ques'onable Relevance

Rodent-‐Specific Mode of Ac1on •  Renal tumors secondary to α-‐2u-‐

globulin nephropathy •  Urinary bladder tumors

secondary to irrita'on •  Mesovarian leiomyomas

secondary to β2 receptor agonists •  Carcinoids secondary to H2

antagonists •  Thyroid follicular tumors •  Uterine endometrial carcinoma

secondary to dopamine agonists •  Leydig cell tumors in rats

secondary to hormonal perturba'ons

Tumors in Unique Rodent Tissues •  Harderian Gland •  Prepu'al Gland •  Clitoral Gland •  Zymbal’s Gland •  Forestomach

Α-‐2u globulin nephropathy Proposed key events

Chemical exposure and binding to α-‐2u globulin ê Accumula'on of the bound α-‐2u in renal tubular epithelial cells ê Cytotoxicity to renal tubular epithelial cells ê Compensatory renal tubular cell prolifera'on ê Development of renal tumors

Α-‐2u globulin nephropathy

Renal Tubular Adenoma

Α-‐2u globulin nephropathy

•  Animals affected – Mature male rat under influence of testosterone produces large amount of α-‐2u globulin

•  Xenobio'cs associated with α-‐2u globulin nephropathy –  JP-‐4 & other jet fuels hexachloroethane –  Isophorone d-‐limonene –  Parachlorobenzene Pentachloroethane –  Unleaded gasoline Nitrotoluene

•  Unaffected mammals –  Female rats Male and female mice Humans – Male NCI-‐Black-‐Reiter rat

Urinary Bladder Tumors

•  Secondary to irrita'on – Mechanical irrita'on from foreign bodies or calculi

•  Affects rats and mice – Threshold effect – only seen at doses of chemical that produce calculi

•  Agents associated with urinary bladder tumors – Uracil Cyclamate – Chronic irrita'on

Urinary Bladder Papilloma

Mesovarian Leiomyomas in Rats •  Seen following administra'on of β2-‐receptor adrenergic s'mulants –  Prolifera'on of mesovarian smooth muscle –  Propanolol (adrenergic blocker) prevents forma'on of this tumor

•  Xenobio'cs causing this effect Salbutamol Terbutaline

•  Specific to the rat – Not seen in mice or hamsters – Not seen in humans with long history of using β2-‐s'mulants

Carcinoids (Neuroendocrine Tumors) in the Rodent Stomach

•  Associated with prolonged blockage of acid secre'on –  Seen for powerful and long-‐las'ng H2-‐receptor antagonists & proton-‐pump inhibitors given at high doses

–  SK&F93479 Omeprazole Butachlor Methyleugenol •  Leads to increased gastrin levels

–  S'mula'on of neuroendocrine cells leading to hyperplasia and neoplasia

–  Slight hypergastrinemia in humans not associated with hyperplasia or neoplasia of neuroendocrine cells

•  Seen at high doses in rodents –  Humans have low serum gastrin levels (margin of safety)

Neuroendocrine Tumor (Carcinoid)

Thyroid Follicular Cell Neoplasms •  Caused by altered feedback mechanism resul'ng in

prolonged s'mula'on of the thyroid by TSH •  Rats vs. humans lack high-‐affinity thyroxin-‐binding globulin,

are more sensi've to inhibi'on of thyroid peroxidase, are more sensi've to hepa'c enzyme induc'on

•  Categories of altered feedback mechanism –  Interference with iodine uptake & thyroid hormone synthesis or secre'on

•  sulfonamides –  Interference with metabolism of T4 or T3

•  FD&C Red No. 3 (erythrosine) –  Increased metabolism & excre'on of thyroid hormones

•  Phenobarbital Polychlorinated biphenyls

Thyroid Follicular Adenoma

Uterine Endometrial Carcinomas in Rats

•  Seen in older rats associated with estrogen dominance

•  Permanent estrus and endometrial s'mula'on – Leads to endometrial carcinoma

•  Seen in rats treated with dopamine agonists – Bromocrip'ne

•  Similar endocrine imbalance does not occur in women

Uterine Endometrial Carcinoma

Leydig Cell Tumors in Rats

•  Interference with Leydig cell control mechanisms (7 different types of interference)

•  All involve the hypothalamic-‐pituitary-‐tes's axis •  Xenobio'cs associated with rat Leydig cell tumors

– Cime'dine Finasteride Flutamide – Gembibrozil Indomethacin DEHP

•  Rats vs humans – Rats have 14 'mes more LH receptors – LHRH receptors unique to the rat

Leydig Cell Tumor

Rodent Tumors of Ques'onable Relevance

Rodent-‐Specific Mode of Ac1on •  Renal tumors secondary to α-‐2u-‐

globulin nephropathy •  Urinary bladder tumors

secondary to irrita'on •  Mesovarian leiomyomas

secondary to β2 receptor agonists •  Carcinoids secondary to H2

antagonists •  Thyroid follicular tumors •  Uterine endometrial carcinoma

secondary to dopamine agonists •  Leydig cell tumors in rats

secondary to hormonal perturba'ons

Tumors in Unique Rodent Tissues •  Harderian Gland •  Prepu'al Gland •  Clitoral Gland •  Zymbal’s Gland •  Forestomach

2-Year Oncogenicity Studies Evaluated

Pesticide database (www.epa.gov/ncct/toxrefdb/)

257 Rat 246 Mouse 281 Total Rodent 1006 Sex/Species

National Toxicology Program database (http://ntp.niehs.nih.gov/)

552 Total Rodent ~2200 Sex/Species

Pesticide Database One study (1 of 281) has an increased incidence of Harderian gland tumors in female mice and forestomach tumors in male and female mice. No other sex/species exposure groups in the 280 other 2-year oncogenicity studies had increased incidences of these rodent only tumors.

NTP database 90 of the 552 studies available for review had increased incidence of at least one of the list of 5 rodent unique tissue tumors in at least one sex/species.

NTP Database Forestomach Female rat 20; Male rat 24; Female mouse 34; Male mouse 29 Zymbal’s gland Female rat 19; Male rat 22; Female mouse 4; Male mouse 3 Harderian gland Male rat 1; Female mouse 15; Male mouse 16 Preputial gland Clitoral gland Male rat 13; Male mouse 5 Female rat 16

NTP Database In 11 cases there was an increased incidence of a single rodent specific tumor in a single sex/species as the only positive neoplastic finding. Female rat: Clitoral gland 2; Zymbal’s gland 1 Male rat: Forestomach 1; Preputial gland 1 Female mouse: Forestomach 4 Male mouse: Forestomach 1

(90/552 positive studies)

Harderian gland Described by Johann Jacob Harder in 1694 Present in terrestrial vertebrates – amphibians to mammals In mammals – not present in cattle, horses, carnivores, higher primates including humans Functional activities include (depending on species) – lubrication, immune response, pheromone production, saliva, osmoregulation, photoreception, thermoregulation, elaboration of growth factors. Has been shown to possess metabolic capability – Cytochrome P450, lipid metabolism, and porphyrin metabolism

Female mice 15 positive studies In one case the only tumor in study. 9/15 involved genotoxic xenobiotics including the study with only positive tumor site Male mice 16 positive studies In one case the only tumor in study 9/16 involved genotoxic xenobiotics including the study with only positive tumor site In the only tumor site cases in mice, both sexes had Harderian gland tumors. Male rat Single study with Harderian gland tumor, multi-site genotoxic carcinogen.

Harderian Gland Tumor

Harderian Gland Adenoma

Effect of Diet on Spontaneous Harderian Gland Tumors

NIH-07 overall incidence

Female mouse

129/3286 3.9%

183/1448 12.6%

Male mouse

175/3286 5.3%

223/1399 15.9%

Male rat

1/3245 0.03%

1/1399 0.07%

Harderian Gland

•  Mul'func'onal gland •  Metabolically ac've •  Spontaneous incidence influenced by diet •  Tumors typically seen in studies where other tumors are associated with treatment

•  Humans do not have Harderian glands

Clitoral gland Preputial gland

Paired Specialized sebaceous glands

Preputial Gland Tumors in NTP Studies

Male mice 5 positive studies All are multisite carcinogens 4/5 are genotoxic 3/5 also had Zymbal’s gland tumors

4/5 had skin and/or Zymbal’s gland tumors Male rat 13 positive studies 2 studies the only tumor in male rat, 1 case only tumor in study 5/13 are genotoxic 5/11 also had Zymbal’s gland tumors 4/11 had skin tumors

5/11 had skin and/or Zymbal’s gland tumors

Female rat 16 positive studies in NTP database 11/16 were genotoxic 4 studies only tumor in female rat,

2 cases only tumor in study 9/12 also had Zymbal’s gland tumors 5/12 also had skin tumors

10/12 had skin and/or Zymbal’s gland tumors 2/4 were positive in male rat preputial gland

Clitoral Gland Tumors in NTP Studies

Clitoral gland Preputial gland

Male mouse

0/3529 0%

2/1394 0.1%

Male rat

274/3348 8.2%

70/1395 5.0%

Female rat

359/3259 11.0%

161/1347 12.0%

Preputial and Clitoral Glands

•  Specialized sebaceous glands

•  Typically associated with other cutaneous tumors

•  In 7 studies both rat preputial (7/13) and clitoral (7/16) gland tumors were present.

•  Spontaneous tumor rates not affected by diet.

•  Not present in humans.

Zymbal’s gland

Modified sebaceous glands along the base of the ear. Possess cytochrome P450 metabolizing enzymes. May be deficient in some phase II metabolizing enzymes

http://www.item.fraunhofer.de/reni

Mouse Zymbal’s gland Mouse skin sebaceous gland

Zymbal’s Gland Tumors NTP Mouse Studies

Female mouse 4 positive studies all multisite carcinogens 2/4 were genotoxic carcinogens

Male mouse

3 positive studies all multisite carcinogens All positive for preputial gland 2/3 were genotoxic carcinogens

Zymbal’s Gland Tumors NTP Rat Studies

Female rat 19 studies positive 14/19 were genotoxic carcinogens 3 were the only female rat tumor in study 6/16 also had skin tumors 9/16 also had clitoral gland tumors 10/16 had clitoral gland and/or skin tumors

Male rat 22 studies positive 16/22 were genotoxic carcinogens 2 were the only male rat tumor in study 16/20 also had skin tumors 5/16 also had preputial gland tumors 16/16 had preputial gland and/or skin tumors

Zymbal’s Gland Carcinoma

Incidence of Zymbal’s gland tumors in Control Rodents Fed NIH-07 Diet

NTP database

Derm acetone

Derm ethanol

Derm Gavage corn oil

Gavage methyl cellulose

Gavage water

Inhalation Feed Water Total and %

Female Rat

1/100 2/301 0/51 1/401 0/100 0/50 6/1052 6/1001 5/330 21/3386 0.6%

Male Rat

1/100 4/302 0/50 2/402 1/101 0/50 15/1055 10/1004 6/331 39/3395 1.2%

Female Mouse

0/150 0/302 nd 26/463

5.6% 0/100 0/51 1/1077 0/953 0/340 26/3436

Male Mouse

0/150 0/299 nd 23/464

5.0% 0/100 0/50 0/1074 0/952 0/340 24/3429

Incidence of Zymbal’s gland tumors in Control Rodents Fed NIH-2000 Diet

NTP database

Derm ethanol

Gavage corn oil

Gavage water

Female Rat

0/150 1/150 0/100 0/150 4/350 1/250 2/200 8/1350

Male Rat

1/150 2/150 0/100 0/150 2/349 4/300 2/200 11/1399

Female Mouse

0/150 0/148 0/100 0/150 0/400 1/300 0/200 1/1448

Male Mouse

0/150 0/150 0/100 0/150 0/400 0/250 0/199 0/1399

FM 5.6% MM 5.0%

Zymbal’s Gland Tumors

•  Modified sebaceous gland

•  Typically associated with other cutaneous tumors

•  Metabolically active site

•  Majority associated with genotoxic carcinogens

•  Decreased diet-related spontaneous tumor rates in mice

Forestomach Papilloma

Forestomach Tumors in NTP Mouse Studies Female mouse

35 studies positive (from 90/552 studies) 22/35 genetox positive 17/35 irritants 28/35 genotoxic or irritant 16 only female mouse tumor 13/16 genetox positive or irritant

Male mouse

30 studies positive 20/30 genetox positive 16/30 irritants 25/30 genotoxic or irritant 8 only male mouse tumor 8/8 genetox positive or irritant

Female rat 20 studies positive (from 90/552 studies) 15/20 genetox positive 10/20 irritants 16/20 genotoxic and/or irritant 9 only female rat tumor 8/9 genotoxic or irritant

Male rat

24 studies positive 18/24 genetox positive 11/24 irritants 21/24 genotoxic and/or irritant 9 only male rat tumor 8/9 genotoxic or irritant

Forestomach Tumors in NTP Rat Studies

Forestomach Tumors by Route of Administration

Female mouse 21/35 Gavage studies

18/21 corn oil 3/21 water

7/35 Feed Male mouse 19/30 Gavage studies

15/19 corn oil 3/19 water 1/19 methyl cellulose

5/30 Feed

Female rat 15/20 Gavage studies

10/15 corn oil 4/15 water 1/15 methyl cellulose

4/20 Feed Male rat 15/24 Gavage studies

11/15 corn oil 4/15 water

8/24 Feed

Incidence of Forestomach tumors in Control Rodents Fed NIH-07 Diet

NTP database

Derm acetone

Derm ethanol

Derm Gavage corn oil

Gavage water

Female Rat

0/100 0/301 0/51 2/401 0/100 0/50 1/1052 2/1001 1/330 6/3386 0.2%

Male Rat

1/100 0/302 2/50 2/402 0/101 0/50 1/1055 0/1004 0/331 6/3395 0.2%

Female Mouse

2/150 1.3%

2/299 0.6%

nd 19/463

4.1% 1/100 1.0%

0/51 0%

10/1077 0.9%

16/953 1.7%

5/340 1.5%

55/3433 1.6%

Male Mouse

2/150 1.3%

6/302 2.0%

nd 22/464

4.7% 0/100 0%

0/50 0%

7/1074 0.7%

14/952 1.5%

4/340 1.2%

55/3432 1.6%

Incidence of Forestomach tumors in Control Rodents Fed 2000 Diet

NTP database

Derm ethanol

Gavage corn oil

Gavage water

Female Rat

0/150 1/150 1/100 1/150 0/350 1/250 1/200 5/1350 0.4%

Male Rat

2/150 0/150 0/100 0/150 0/349 0/300 1/200 3/1399 0.2%

Female Mouse

3/150 2.0%

2.7% 1/100 1.0%

3/150 2.0%

6/400 1.5%

5/300 1.7%

3/200 1.5%

25/1448 1.7%

Male Mouse

1/150 1/150

0.7% 2/100 3/150 4/400 4/250 3/199 18/1399

FM 4.1% MM 4.7%

Forestomach Tumors •  Susceptible to local combination of chronic wounding (irritation)

and mutagenicity •  More likely to develop from direct exposure; more likely in gavage

studies

•  Metabolically active site

•  Decreased diet-related spontaneous tumor rate in mice

•  In 8/9 and 9/9 cases of only tumor in male or female rats, respectively, also tumor in opposite sex.

•  In 7/8 and 12/16 cases of only tumor in male or female mice, respectively, also tumor in opposite sex.

Site Concordance

Target organ concordance need not be a prerequisite for evaluating the implications of animal study results for humans. There is evidence that growth control mechanisms at the level of the cell are homologous among mammals, but these mechanisms are not necessarily site concordant.

Site Concordance

Target organ concordance need not be a prerequisite for evaluating the implications of animal study results for humans. There is evidence that growth control mechanisms at the level of the cell are homologous among mammals, but these mechanisms are not necessarily site concordant.

Tumors in Unique Rodent Tissues

•  Harderian Gland •  Prepu'al Gland •  Clitoral Gland •  Zymbal’s Gland •  Forestomach

Concerns about the significance of these to human cancer risk can be addressed using the mode of action/human relevance framework approach. <

Rodent Cancer Study Databases

Pesticide database (www.epa.gov/ncct/toxrefdb/) National Toxicology Program database (http://ntp.niehs.nih.gov/)

Xenobio’c)induced,Rodent Tumors,of,Ques’onable ... · Relevance,...

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