ToxSci Advance Access originally published online on March 19, 2007
Toxicological Sciences 2007 97(2):548-561; doi:10.1093/toxsci/kfm059
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Recombinant Rat and Mouse Growth Hormones: Risk Assessment of Carcinogenic Potential in 2-Year Bioassays in Rats and Mice
* Department of Safety Assessment, Merck Research Laboratories, West Point, Pennsylvania 19486
Merck Sharp & Dohme-Chibret Laboratories, Research Center, Department of Safety Assessment, 63203 Riom, France
Merck Research Laboratories, Department of Immunology, West Point, Pennsylvania 19486
1 To whom correspondence should be addressed at Department of Safety Assessment, Merck Research Laboratories, Merck & Co., Inc., WP81-402, Sumneytown Pike, West Point, PA 19486. Fax: (215) 993-7748. E-mail: georgia_farris{at}merck.com.
Received December 20, 2006; accepted March 13, 2007
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Abstract |
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Recombinant rat growth hormone (rrGH) and recombinant mouse growth hormone (rmGH) were developed to evaluate the potential carcinogenicity of each biologically active growth hormone (GH) as assessed in the respective species. Biological activities of rrGH and rmGH were demonstrated by showing an increase in body weight gain and serum levels of insulin-like growth factor-1 (IGF-1) in hypophysectomized rats receiving daily sc injections for 6 days. With the exception of pharmacologically mediated weight gain, rrGH and rmGH had no adverse effects in 5-week oral toxicity studies and no production of anti-recombinant GH antibodies. The high doses selected for the carcinogenicity studies provided systemic exposures of GH up to approximately 10-fold over basal levels. In the 105-week mouse carcinogenicity study, daily sc injections of rmGH at 0.1, 0.2, or 0.5 mg/kg/day were well tolerated and had no effects on survival or incidence of tumors. In the 106-week rat carcinogenicity study, daily sc injections of rrGH at 0.2, 0.4, or 0.8 mg/kg/day had a favorable effect on longevity in female rats administered 0.4 or 0.8 mg/kg/day, an increased weight gain in females and males, and no increase in the incidence of tumors. The absence of carcinogenic effects of recombinant GH administered daily for 2 years to rodents was consistent with publications of clinical experience, indicating a lack of convincing evidence for an increased risk of cancer in children receiving human recombinant GH replacement therapy.
Key Words: risk assessment; endocrine; pharmaceuticals.
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