A Lifetime Oncogenicity Study in Rats with Acrylamide

Abstract A lifetime oncogenicity study in Fischer 344 rats was conducted to accurately characterize the carcinogenic potency of acrylamide. Acrylamide was administered in drinking water throughout the 106-week study at concentrations required to provide a dose of 0, 0.1, 0.5, or 2.0 mg/kg/day to males or 0, 1.0, or 3.0 mg/kg/day to females. Complete necropsy and gross pathology examinations were performed on all study animals. Histopathology examinations were conducted on selected tissues of all high-dose and control animals. Selected tissues from intermediate and low-dose groups were subjected to histopathological examinations as required to clarify high- and controldose group observations. There was no visual observation of neurotoxicity in any study animal but sciatic nerve degeneration was observed in the male and female high-dose groups. Increased mortality related to acrylamide was observed in the high- dose male group from Month 17 to the end of the study and in the high-dose females during Month 24. Mesotheliomas of the testicular tunic were significantly increased in the high-dose male group. The combined incidence of mammary gland adenocarcinomas and fibroadenomas was significantly increased in both acrylamide-dosed female groups. Males and females in the high-dose groups as well as females of the low-dose group had significantly (p<0.001) increased thyroid follicular cell adenomas and adenocarcinomas. A variety of other tumor types observed with increased incidence in a previous acrylamide onco genicity study (i.e., combined CNS glial neoplasms, papillomas of the oral cavity, adenomas of the clitoral gland, and uterine adenocarcinomas) were not observed to be present at increased incidence in this study. This study confirms previously described acrylamide induction of benign tumors of the thyroid and mammary glands as well as mesotheliomas of the testis. By using a larger number of animals with an unbalanced study design, this study showed that acrylamide did not induce glial tumors and demonstrated that the no-observable-effect level for scrotal mesotheliomas is 0.5 mg/kg. It also demonstrated that the in creased incidence of mammary tumors was again within historical control ranges.

[1]  E. Kaplan,et al.  Nonparametric Estimation from Incomplete Observations , 1958 .

[2]  P. Spencer,et al.  A Review of Acrylamide Neurotoxicity Part I. Properties, Uses and Human Exposure , 1974, Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques.

[3]  R. Bull,et al.  A combined carcinogen bioassay utilizing both the lung adenoma and skin papilloma protocols. , 1986, Environmental health perspectives.

[4]  J. Barnes,et al.  Peripheral Neuropathy in Rats Produced by Acrylamide , 1966, British journal of industrial medicine.

[5]  G. Bond,et al.  Acrylamide cohort mortality study. , 1986, British journal of industrial medicine.

[6]  C. Carrington,et al.  In vitro binding of [14C]acrylamide to neurofilament and microtubule proteins of rats , 1989, Brain Research.

[7]  R. Bull,et al.  Carcinogenic activity of acrylamide in the skin and lung of Swiss-ICR mice. , 1984, Cancer letters.

[8]  M. Key.  National Institute for Occupational Safety and Health; occupational exposure to inorganic lead: request for comments and information; republication--NIOSH. Request for comments and information relevant to occupational exposure to inorganic lead. , 1997, Federal register.

[9]  R. Tarone,et al.  Tests for trend in life table analysis , 1975 .

[10]  R. Garman.  Malignant Reticulosis, Rat , 1988 .

[11]  Y. Shiraishi.  Chromosome aberrations induced by monomeric acrylamide in bone marrow and germ cells of mice. , 1978, Mutation research.

[12]  A. Fossa,et al.  Binding and distribution studies in the SENCAR mouse of compounds demonstrating a route-dependent tumorigenic effect. , 1986, Environmental health perspectives.

[13]  N. Bikales.  Preparation of Acrylamide Polymers , 1973 .

[14]  P. Spencer,et al.  Ultrastructural studies of the dying-back process. III. The evolution of experimental peripheral giant axonal degeneration. , 1977, Journal of neuropathology and experimental neurology.

[15]  C. Wade,et al.  Subchronic toxicity of acrylamide administered to rats in the drinking water followed by up to 144 days of recovery. , 1980, Journal of environmental pathology and toxicology.

[16]  J Wahrendorf,et al.  Guidelines for simple, sensitive significance tests for carcinogenic effects in long-term animal experiments. , 1980, IARC monographs on the evaluation of the carcinogenic risk of chemicals to humans. Supplement.

[17]  D. W. Sickles.  Toxic neurofilamentous axonopathies and fast anterograde axonal transport. IV. In vitro analysis of transport following acrylamide and 2,5-hexanedione. , 1992, Toxicology letters.

[18]  T. J. West,et al.  Water-Soluble Polymers in Petroleum Recovery , 1973 .

[19]  D. Whitaker,et al.  The mesothelium and its reactions: a review. , 1982, Critical reviews in toxicology.

[20]  P. Armitage.  Tests for Linear Trends in Proportions and Frequencies , 1955 .

[21]  W. G. Cochran.  Some Methods for Strengthening the Common χ 2 Tests , 1954 .

[22]  W. Lijinsky,et al.  Mutagenicity of vinyl compounds in Salmonella typhimurium. , 1980, Teratogenesis, carcinogenesis, and mutagenesis.

[23]  Tilson Ha,et al.  Assessment of chemicals using a battery of neurobehavioral tests: a comparative study. , 1983 .

[24]  R J Bull,et al.  Carcinogenic effects of acrylamide in Sencar and A/J mice. , 1984, Cancer research.

[25]  R. D. Howland,et al.  Altered phosphorylation of rat neuronal cytoskeletal proteins in acrylamide induced neuropathy , 1986, Brain Research.

[26]  J M Ward,et al.  Neoplastic and nonneoplastic lesions in aging F344 rats. , 1979, Toxicology and applied pharmacology.

[27]  G. Kelloff,et al.  Incidence of spontaneous neoplasms in F344 rats throughout the natural life-span. , 1975, Journal of the National Cancer Institute.

[28]  P. Sager.  Cytoskeletal effects of acrylamide and 2,5-hexanedione: selective aggregation of vimentin filaments. , 1989, Toxicology and applied pharmacology.

[29]  Joseph K. Haseman,et al.  Use of Historical Control Data in Carcinogenicity Studies in Rodents , 1984, Toxicologic pathology.

[30]  Keith A. Johnson,et al.  Chronic toxicity and oncogenicity study on acrylamide incorporated in the drinking water of Fischer 344 rats. , 1986, Toxicology and applied pharmacology.

[31]  H. Zenick,et al.  Reproductive toxicity associated with acrylamide treatment in male and female rats. , 1986, Journal of toxicology and environmental health.

[32]  D. W. Sickles.  Toxic neurofilamentous axonopathies and fast anterograde axonal transport. I. The effects of single doses of acrylamide on the rate and capacity of transport. , 1991, Neurotoxicology.

[33]  D. W. Sickles.  Toxic neurofilamentous axonopathies and fast anterograde axonal transport. III. Recovery from single injections and multiple dosing effects of acrylamide and 2,5-hexanedione. , 1991, Toxicology and applied pharmacology.

[34]  N. Mantel.  Evaluation of survival data and two new rank order statistics arising in its consideration. , 1966, Cancer chemotherapy reports.

[35]  Gregg E. Dinse,et al.  Regression Analysis of Tumour Prevalence Data , 1983 .

[36]  H. Wiśniewski,et al.  ULTRASTRUCTURAL STUDIES OF THE DYING‐BACK PROCESS: 1. PERIPHERAL NERVE TERMINAL AND AXON DEGENERATION IS SYSTEMIC ACRYLAMIDE INTOXICATION , 1974, Journal of neuropathology and experimental neurology.

[37]  J. Solomon,et al.  Direct alkylation of 2'-deoxynucleosides and DNA following in vitro reaction with acrylamide. , 1985, Cancer research.

[38]  R. J. Preston,et al.  Dominant lethal effects of subchronic acrylamide administration in the male Long-Evans rat. , 1986, Mutation research.

[39]  H. Onodera,et al.  Spontaneous Mesotheliomas in Fischer Rats—A Histological and Electron Microscopic Study , 1987, Toxicologic pathology.

[40]  H. A. Solleveld,et al.  Guidelines for combining neoplasms for evaluation of rodent carcinogenesis studies. , 2010, Journal of the National Cancer Institute.

[41]  J K Haseman,et al.  Natural history of body weight gain, survival, and neoplasia in the F344 rat. , 1984, Journal of the National Cancer Institute.

[42]  F. Turek,et al.  Development of Leydig cell tumors and onset of changes in the reproductive and endocrine systems of aging F344 rats. , 1979, Journal of the National Cancer Institute.

[43]  G. Krinke,et al.  The incidence of naturally-occurring primary brain tumours in the laboratory rat. , 1985, Journal of comparative pathology.

[44]  G. Swaen,et al.  Mortality patterns among workers exposed to acrylamide. , 1989, Journal of occupational medicine. : official publication of the Industrial Medical Association.