Comparative pathophysiology, toxicology, and human cancer risk assessment of pharmaceutical-induced hibernoma

Journal Article · Sun Dec 15 04:00:00 EST 2013 · Toxicology and Applied Pharmacology

DOI:https://doi.org/10.1016/J.TAAP.2013.10.011· OSTI ID:22285525

Radi, Zaher ^[1]; Bartholomew, Phillip ^[2]; Elwell, Michael ^[3]

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1. Pfizer Worldwide Research and Development, Drug Safety R and D, 1 Burtt Rd., Andover, MA 01810 (United States)
2. Pfizer Worldwide Research and Development, Drug Safety R and D, Eastern Point Road, Groton, CT 06340 (United States)
3. Covance Laboratories, Chantilly, VA 20151 (United States)

In humans, hibernoma is a very rare, benign neoplasm of brown adipose tissue (BAT) that typically occurs at subcutaneous locations and is successfully treated by surgical excision. No single cause has been accepted to explain these very rare human tumors. In contrast, spontaneous hibernoma in rats is rare, often malignant, usually occurs in the thoracic or abdominal cavity, and metastases are common. In recent years, there has been an increased incidence of spontaneous hibernomas in rat carcinogenicity studies, but overall the occurrence remains relatively low and highly variable across studies. There have only been four reported examples of pharmaceutical-induced hibernoma in rat carcinogenicity studies. These include phentolamine, an alpha-adrenergic antagonist; varenicline, a nicotine partial agonist; tofacitinib, a Janus kinase (JAK) inhibitor; and hydromorphone, an opiod analgesic. Potential non-genotoxic mechanisms that may contribute to the pathogenesis of BAT activation/proliferation and/or subsequent hibernoma development in rats include: (1) physiological stimuli, (2) sympathetic stimulation, (3) peroxisome proliferator-activated receptor (PPAR) agonism, and/or (4) interference or inhibition of JAK/Signal Transducer and Activator of Transcription (JAK/STAT) signaling. The evaluation of an apparent increase of hibernoma in rats from 2-year carcinogenicity studies of novel pharmaceutical therapeutics and its relevance to human safety risk assessment is complex. One should consider: the genotoxicity of the test article, dose/exposure and safety margins, and pathophysiologic and morphologic differences and similarities of hibernoma between rats and humans. Hibernomas observed to date in carcinogenicity studies of pharmaceutical agents do not appear to be relevant for human risk at therapeutic dosages. - Highlights: • Highly variable incidence of spontaneous hibernoma in carcinogenicity studies • Recent increase in the spontaneous incidence of hibernomas in Sprague–Dawley rats • Pharmaceutical-related hibernoma has been observed in rats, but not in humans. • Pathophysiologic and morphologic differences of hibernoma between rats and 7 humans. • Hibernomas are unlikely to be relevant to human risk assessment.

• OSTI ID: 22285525
• Journal Information: Toxicology and Applied Pharmacology, Journal Name: Toxicology and Applied Pharmacology Journal Issue: 3 Vol. 273; ISSN TXAPA9; ISSN 0041-008X
• Country of Publication: United States
• Language: English

Related Subjects

60 APPLIED LIFE SCIENCES
ADIPOSE TISSUE
ANALGESICS
METASTASES
NEOPLASMS
NICOTINE
PATHOGENESIS
RATS
RECEPTORS
RISK ASSESSMENT
SAFETY MARGINS
TOXICITY