Toxicology and carcinogenesis studies of acrylamide (CASRN 79-06-1) in F344/N rats and B6C3F1 mice (feed and drinking water studies).

Acrylamide, a water-soluble α,β-unsaturated amide, is a contaminant in baked and fried starchy foods, including french fries, potato chips, and bread, as a result of Maillard reactions involving asparagine and reducing sugars. Additional sources of acrylamide exposure include cigarettes, laboratory procedures involving polyacrylamide gels, and various occupations (e.g, monomer production and polymerization processes). Acrylamide is carcinogenic in experimental animals. To obtain data for developing quantitative risk assessments for dietary exposures to acrylamide, the Food and Drug Administration nominated acrylamide for an in-depth toxicological evaluation by the National Toxicology Program. As part of this evaluation, male and female B6C3F1/Nctr (C57BL/6N x C3H/HeN MTV-) mice and male and female F344/N Nctr rats were exposed to acrylamide (at least 99.4% pure) in drinking water for 2 years. 2-WEEK STUDY IN RATS: Groups of four male and four female F344/N rats were administered 0, 0.14, 0.35, 0.70, 1.41, 3.52, or 7.03 mM acrylamide in the drinking water (0, 10, 25, 50, 100, 250, or 500 ppm acrylamide) or 0.0, 7.4, 18.5, 37, 74, 185, or 370 mg acrylamide per kg diet for 14 days. One male rat administered 7.03 mM acrylamide in the drinking water died on day 14. Male and female rats receiving 7.03 mM acrylamide weighed 56% and 64% of controls, respectively. Male and female rats fed 370 mg acrylamide per kg diet weighed 74% and 83% of controls, respectively. Female rats receiving 3.52 mM acrylamide in drinking water and male rats fed 185 mg acrylamide per kg diet weighed 85% and 89% of controls, respectively. Rats receiving 7.03 mM acrylamide in drinking water or 370 mg acrylamide per kg diet exhibited hind-leg paralysis on day 14. Mild to moderate dilatation of the urinary bladder was observed in all rats given 370 mg acrylamide per kg diet, and in three of four male rats and all four female rats given 7.03 mM acrylamide in drinking water, and in one of four male rats given 3.52 mM acrylamide in drinking water. Mild to moderate degeneration of the germinal epithelium in the seminiferous tubules of the testes was noted microscopically in all male rats given 7.03 mM acrylamide in drinking water and in two of four male rats fed 370 mg acrylamide per kg diet. 2-WEEK STUDY IN MICE: Groups of four male and four female B6C3F1 mice were administered 0, 0.14, 0.35, 0.70, 1.41, 3.52, or 7.03 mM acrylamide in the drinking water (0, 10, 25, 50, 100, 250, or 500 ppm acrylamide) or 0.0, 7.4, 18.5, 37, 74, 185, or 370 mg acrylamide per kg diet for 14 days. None of the mice administered 7.03 mM acrylamide in the drinking water survived the 14-day study. Mice administered 7.03 mM acrylamide in the drinking water showed marked decreases in body weight (greater than 25% compared to control mice) after seven days of treatment, and two of the mice displayed hind leg paralysis. No significant adverse effects were observed in mice administered 3.52 mM acrylamide in the drinking water for 14 days. Female B6C3F1 mice given 370 mg acrylamide per kg diet for 14 days showed a modest decrease (11%) in body weight. No other significant adverse effects were observed in mice administered any dose of acrylamide in the diet. 3-MONTH STUDY IN RATS: Groups of eight male and eight female F344/N rats were administered 0.0, 0.14, 0.35, 0.70, 1.41, or 3.52 mM acrylamide in the drinking water (0, 10, 25, 50, 100, or 250 ppm acrylamide) or 0.0, 7.4, 18.5, 37, 74, or 185 mg acrylamide per kg diet for 13 weeks. After 13 weeks, male and female rats administered 3.52 mM acrylamide weighed 73% and 71% of the control rats, respectively. Male and female rats fed 185 mg acrylamide per kg diet for 13 weeks weighed 86% and 82% of the control rats, respectively. Hind-leg paralysis was observed in all rats administered 3.52 mM acrylamide in the drinking water or 185 mg acrylamide per kg diet. Four of eight female rats administered 1.41 mM acrylamide also displayed hind-leg paralysis. Radiculoneuropathy (a degenerative lesion) involving the sciatic nerve and lumbar spinal cord was observed in all male and female rats administered 3.52 mM acrylamide or 185 mg acrylamide per kg diet. A low incidence of radiculoneuropathy was also noted in female rats fed 74 mg acrylamide per kg diet. The neuronal degenerative changes were accompanied, at times, by atrophy in skeletal muscle of the hind-limb and luminal dilation of the urinary bladder. All rats treated with 3.52 mM acrylamide displayed increased hemosiderin pigment in their spleens and hyperplasia of red blood cell precursors in their bone marrow. Two of eight male rats fed 185 mg acrylamide per kg diet also had increased hemosiderin pigment in their spleens. Degeneration of the germ cells in the testes was observed in all male rats given 1.41 or 3.52 mM acrylamide, or 185 mg acrylamide per kg diet. A lower incidence of this lesion was also detected in all other doses of acrylamide in the diet. 3-MONTH STUDY IN MICE: Groups of eight male and eight female B6C3F1 mice were administered 0, 0.14, 0.35, 0.70, 1.41, or 3.52 mM acrylamide in the drinking water (0, 10, 25, 50, 100, or 250 ppm acrylamide) or 0.0, 18.5, 37, 74, 185, or 370 mg acrylamide per kg diet. After 13 weeks, the male and female mice given 3.52 mM acrylamide weighed 86% and 94% of their respective control mice; male mice administered 1.41 mM acrylamide weighed 91% of the control male mice; and male and female mice fed 370 mg acrylamide per kg diet weighed 87% and 81% of their respective control groups. Hind-limb paralysis was observed in all mice administered 3.52 mM acrylamide or 370 mg acrylamide per kg diet. Radiculoneuropathy involving the sciatic nerve, lumbar spinal cord, or both was observed in all male and female mice administered 3.52 mM acrylamide. Radiculoneuropathy, involving primarily the sciatic nerve, was also noted in one of eight female mice fed 185 mg acrylamide per kg diet and in mice fed 370 mg acrylamide per kg diet. The neuronal degenerative changes were accompanied, at times, by atrophy in skeletal muscle of the hind-limb and luminal dilation of the urinary bladder. Degeneration of the germ cells in the testes was observed in six of eight male mice given 3.52 mM acrylamide and seven of seven mice fed 370 mg acrylamide per kg diet. 2 YEAR STUDY IN RATS: Groups of 48 male and 48 female F344/N rats were administered acrylamide in the drinking water ad libitum for 2 years. Concentrations of 0.0875, 0.175, 0.35, and 0.70 mM acrylamide (6.25, 12.5, 25, and 50 ppm acrylamide) resulted in an average daily consumption of approximately 0.33, 0.66, 1.32, and 2.71 mg acrylamide per kg body weight in male F344/N rats and 0.44, 0.88, 1.84, and 4.02 mg acrylamide per kg body weight in female F344/N rats. Acrylamide had no effect upon the survival of male F344/N rats. Female F344/N rats administered 0.175, 0.35, or 0.70 mM acrylamide had decreased survival compared to control female F344/N rats. Acrylamide caused significant dose-related decreasing trends in body weight in F344/N rats. At the end of the 2 year period, male and female F344/N rats administered 0.70 mM acrylamide weighed 86% and 85% of their respective control groups. Feed consumption was generally not affected by acrylamide; water consumption in female F344/N rats was increased at later time points. In male F344/N rats, the incidence of epididymis malignant mesothelioma, combined epididymis or testicular tunica malignant mesothelioma, heart malignant incidences of schwannoma, pancreatic islets adenoma, thyroid gland follicular cell carcinoma, and combined thyroid gland follicular cell adenoma or carcinoma was increased significantly in the 0.70 mM acrylamide group. In female F344/N rats, the incidence of clitoral gland carcinoma was increased significantly in the 0.0875, 0.175, and 0.70 mM acrylamide groups. The incidence of mammary gland fibroadenoma was increased significantly at 0.175, 0.35, and 0.70 mM acrylamide. Significant increases in neoplasm incidences were also observed in oral mucosa squamous cell papilloma, combined oral mucosa or tongue squamous cell papilloma or carcinoma, combined skin fibroma, fibrosarcoma, or sarcoma, and combined thyroid gland follicular cell adenoma or carcinoma at 0.70 mM acrylamide. 2-YEAR STUDY IN MICE: Groups of 48 male and 48 female B6C3F1 mice were administered acrylamide in the drinking water ad libitum for 2 years. Concentrations of 0.0875, 0.175, 0.35, and 0.70 mM acrylamide (6.25, 12.5, 25, and 50 ppm acrylamide) resulted in average daily consumption of approximately 1.04, 2.20, 4.11, and 8.93 mg acrylamide per kg body weight in male B6C3F1 mice and 1.10, 2.23, 4.65, and 9.96 mg acrylamide per kg body weight in female B6C3F1 mice. Acrylamide caused dose-related decreasing trends in survival in B6C3F1 mice, with the survival being significantly decreased in male B6C3F1 mice administered 0.70 mM acrylamide and female B6C3F1 mice given 0.35 and 0.70 mM acrylamide. Acrylamide caused only sporadic changes in body weight in B6C3F1 mice, with the magnitude of the change never exceeding 6% of the respective control body weight. Food and water consumption was generally not affected by acrylamide, except for an increased consumption by female B6C3F1 mice in the 0.70 mM acrylamide group toward the end of the study. In male B6C3F1 mice, the incidence of harderian gland adenoma and combined harderian gland adenoma or adenocarcinoma was increased significantly in all acrylamide dose groups. The incidence of lung alveolar/bronchiolar adenoma and combined lung alveolar/bronchiolar adenoma or carcinoma was increased significantly at 0.175 and 0.70 mM acrylamide, and the incidence of stomach (forestomach) squamous cell papilloma and combined stomach (forestomach) squamous cell papilloma or carcinoma was increased significantly at 0.35 and 0.70 mM acrylamide. (ABSTRACT TRUNCATED)