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PubMed1991

NTP Toxicology and Carcinogenesis Studies of Tris(2-chloroethyl) Phosphate (CAS No. 115-96-8) in F344/N Rats and B6C3F1 Mice (Gavage Studies).

Tris(2-chloroethyl) phosphate (TRCP), a flame-retardant plasticizer used in plastics, polymeric foams, and synthetic fibers, was studied as part of the National Toxicology Program's class study of trisalkyl phosphate flame retardants. Toxicology and carcinogenesis studies were conducted by administering TRCP (approximately 98% pure) in corn oil by gavage to groups of F344/N rats and B6C3F1 mice of each sex for 16 days, 16 weeks, or 2 years. Genetic toxicology studies were performed in Salmonella typhimurium and Chinese hamster ovary (CHO) cells. 16-Day Studies: There were no chemical-related deaths, differences in final mean body weight, or histopathological lesions in rats receiving 22 to 350 mg/kg TRCP or in mice receiving 44 to 700 mg/kg TRCP for 12 doses over 16 days. Serum cholinesterase activity in female rats receiving 175 or 350 mg/kg TRCP was reduced slightly (80% of control levels), but enzyme activity in dosed male rats and in mice was similar to that in controls. 16-Week Studies: Rats received 22 to 350 mg/kg TRCP for 16 weeks (female) or 18 weeks (male). Several male and female rats in the 175 or 350 mg/kg dose groups died from chemical toxicity. Final mean body weights of female rats receiving 350 mg/kg were 20% greater than those of controls; final mean body weights of the remaining groups of dosed female rats and dosed male rats were similar. Chemical-related neuronal necrosis occurred in the hippocampus and thalamus of female rats and, to a lesser extent, of male rats. Serum cholinesterase activity was reduced in females receiving 175 or 350 mg/kg TRCP. There were no chemical-related deaths, differences in final mean body weight, or differences in cholinesterase activity in mice receiving 44 to 700 mg/kg TRCP for 16 weeks. Tubule epithelial cells with enlarged nuclei (cytomegaly and karyomegaly) were observed in the kidneys of high-dose (700 mg/kg) male and female mice. 2-Year Studies: The 2-year studies in rats were conducted by administering 0, 44, or 88 mg/kg TRCP to groups of 60 males and females, 5 days per week for up to 104 weeks; 9 or 10 rats of each dose group were evaluated at 66 weeks. The survival of high-dose male and female rats was reduced relative to that of controls. Final mean body weights of surviving rats were similar to those of controls. The principal chemical-related effects occurred in the kidney and brain of dosed rats. Focal hyperplasia of the renal tubule epithelium and renal tubule adenomas were markedly increased in male rats receiving 88 mg/kg TRCP and, to a lesser extent, in female rats (renal tubule hyperplasia, male rats: 0/50; 2/50; 24/50; female rats: 0/50; 3/50; 16/50; renal tubule adenoma, male rats: 1/50; 5/50; 24/50; female rats: 0/50; 2/50; 5/50). Renal tubule carcinomas occurred in one control and one high-dose male rat. Degenerative lesions consisting of gliosis, mineralization, hemorrhage, and/or hemosiderin accumulation occurred in the cerebrum and brain stem of more than 50% of female rats receiving 44 or 88 mg/kg TRCP; similar lesions were seen in only a few dosed males. Slightly increased incidences of thyroid gland follicular cell neoplasms (male rats: 5/50; 14/50; 13/50; female rats: 14/50; 16/50; 20/50) occurred in dosed males and females, but it is uncertain whether these were related to chemical administration. The 2-year studies in mice were conducted by administering 0, 175, or 350 mg/kg TRCP to groups of 60 males and females, 5 days per week for up to 104 weeks; 8 to 10 mice of each sex per dose group were evaluated at 66 weeks. There were no significant differences in survival between dosed and control groups of either sex, and final mean body weights of mice were similar among all groups. The principal chemical-related effects occurred in the kidney, in which nuclear enlargement (karyomegaly) of tubule epithelial cells was present in approximately 80% of high-dose mice. In the original diagnosis, renal tubule adenomas were seen in one control male, one high-dose male, and one low-dose female. A carcinoma was also seen in one high-dose male. In a s seen in one high-dose male. In a subsequent examination of step sections of all the mouse kidneys, adenomas were found in one low-dose male and two high-dose males. The incidences of renal tubule neoplasms in the original and step sections combined were 1/50, 1/50, and 4/50 for males. Female mice receiving TRCP demonstrated a marginally increased incidence of neoplasms (primarily adenomas) of the harderian gland (3/50; 8/50; 7/50); in addition, three harderian gland neoplasms occurred in high-dose female mice evaluated after 66 weeks. Genetic Toxicology: TRCP was not mutagenic in Salmonella typhimurium strains TA100, TA1535, TA1537, or TA98 with or without exogenous metabolic activation (S9), and it tested negative for the induction of chromosomal aberrations in Chinese hamster ovary (CHO) cells. TRCP produced an equivocal response in the presence of S9 for the induction of sister chromatid exchanges (SCE) in CHO cells. Conclusions: Under the conditions of these 2-year gavage studies, there was clear evidence of carcinogenic activity for male and female F344/N rats receiving tris(2-chloroethyl)phosphate as shown by increased incidences of renal tubule adenomas. Thyroid follicular cell neoplasms and mononuclear cell leukemia in male and female rats may have been related to chemical administration. There was equivocal evidence of carcinogenic activity for male B6C3F1 mice as shown by a marginally increased incidence of renal tubule cell neoplasms. There was equivocal evidence of carcinogenic activity for female B6C3F1 mice as shown by a marginally increased incidence of harderian gland adenomas. Renal tubule cell hyperplasia in male and female rats and gliosis, hemorrhage, pigmentation (hemosiderin accumulation), and mineralization in the brains of female rats were associated with the administration of tris(2-chloroethyl) phosphate. Karyomegaly of renal tubule epithelial cells in male and female mice was also chemical related. Synonyms: 2-chloroethanol phosphate (3:1); tris(b-chloroethyl) phosphate Trade Names: Fyrol CEF; Disflamoll TCA; NIAX flame retardant

Journal Article↗
PubMed1991

NTP Toxicology and Carcinogenesis Studies of 3,3'-Dimethylbenzidine Dihydrochloride (CAS No. 612-82-8) in F344/N Rats (Drinking Water Studies).

3,3'-Dimethylbenzidine dihydrochloride is one of five chemicals being evaluated in 2-year carcinogenicity and toxicity studies as part of the NTP's Benzidine Dye Initiative. This Initiative was designed to evaluate representative benzidine congeners, benzidine congener-derived dyes, and benzidine-derived dyes. 3,3'-Dimethylbenzidine dihydrochloride was nominated for study because of the potential for human exposure during production of bisazobiphenyl dyes and because benzidine, a structurally related chemical, is a known human carcinogen. Toxicology and carcinogenesis studies were conducted by administering 3,3'-dimethylbenzidine dihydrochloride (approximately 99% pure) in drinking water to groups of F344/N rats of each sex for 14 days, 13 weeks, or 9 or 14 months. The 14-month exposures were planned as 24-month exposures but were terminated early because of rapidly declining animal survival, due primarily to neoplasia. These studies were performed only in rats because similar studies were being performed in mice at the National Center for Toxicological Research (NCTR). Hematologic and serum chemical analyses and thyroid hormone determinations were conducted in conjunction with the 13-week and 9-month studies. Genetic toxicology studies were conducted in Salmonella typhimurium, Chinese hamster ovary (CHO) cells, and Drosophila melanogaster. 14-Day Studies: Rats were exposed to 3,3'-dimethylbenzidine dihydrochloride in drinking water at doses ranging from 600 to 7,500 ppm. All five males and one female in the 7,500 ppm group and 1/5 males in the 5,000 ppm group died. Final mean body weights were decreased in males receiving 1,250 ppm or more and in all exposed females, and final mean body weights of animals receiving 2,500 ppm or more were lower than initial weights. Water consumption decreased with increasing chemical concentration. Compound-related effects observed in rats receiving 5,000 ppm or more included minimal to slight hepatocellular necrosis, accumulation of brown pigment (presumably bile) in individual hepatocytes, increased severity of nephropathy relative to controls, and severe lymphocytic atrophy of the thymus. Treated animals also showed an increased severity of atrophy of the bone marrow relative to controls, varying degrees of lymphocytic atrophy of the mandibular and mesenteric lymph nodes and spleen, increased vacuolization and necrosis of cells of the adrenal cortex, focal acinar cell degeneration in the pancreas, and, in males, increased immature sperm forms in the testis and epididymis. 13-Week Studies: 3,3'-Dimethylbenzidine dihydrochloride was administered in drinking water at doses of 300, 500, 1,000, 2,000, and 4,000 ppm. All rats receiving 4,000 ppm and 4/10 males and 1/10 females receiving 2,000 ppm died before the end of the studies. Depressions in final mean body weight relative to controls ranged from 12% to 48% for males and from 9% to 42% for females. Water consumption decreased with increasing dose. At compound concentrations of 300 to 2,000 ppm, mean water consumption was 29% to 83% of control values. Compound-related effects included an increase in the severity of nephropathy relative to controls; hepatocellular necrosis and accumulation of brown pigment (presumably bile) in sinusoidal lining cells; lymphocytic atrophy of the thymus, spleen, and mandibular and mesenteric lymph nodes; atrophy of the bone marrow in the higher-dose groups; degeneration of pancreatic acinar cells; and, in males, immature sperm forms in the testis and epididymis. Decreases in serum triiodothyronine (T3) values were observed in exposed females, and decreases in mean thyroxin (T4) concentrations in exposed males and females; no significant changes were observed in thyroid stimulating hormone (TSH) levels in exposed rats. Based on the decreased survival, reductions in water consumption and body weight gain, and chemical-induced hepatocellular and renal lesions observed in the 13-week studies, the doses selected for the 9- and 14-month drinking water studies of 3,3'-dimethylbenzidine dihydrochloride were 0, 3 3,3'-dimethylbenzidine dihydrochloride were 0, 30, 70, and 150 ppm. Seventy rats of each sex were used in the control group, 45 in the low-dose group, 75 in the mid-dose group, and 70 in the high-dose group. 9-Month Studies: Ten rats of each sex in the control and 150 ppm dose groups were evaluated after 9 months. Chemical-related effects observed in exposed animals included alveolar/bronchiolar carcinoma in one male, basal cell carcinoma of the skin in one male, a squamous cell carcinoma of the oral cavity in one female, preputial gland carcinoma in two males, clitoral gland carcinoma in three females, adenocarcinoma of the small intestine in two males, Zymbal's gland carcinoma in two males and three females, hepatocellular carcinoma in two males, and adenomatous polyps of the large intestine in three males. Other effects seen in dosed rats included focal cellular alteration in the liver, lymphoid atrophy in the spleen, and increased severity of nephropathy relative to controls. An increase in serum T3 values was observed in exposed males, and a decrease in mean T4 concentrations in exposed males and females. TSH concentrations were increased in exposed male and female rats. Body Weights and Survival in the 14-Month Studies: The average amount of 3,3'-dimethylbenzidine dihydrochloride consumed per day was approximately 1.8, 4.0, or 11.2, mg/kg for low-, mid-, or high-dose male rats and 3.0, 6.9, or 12.9 mg/kg for low-, mid-, or high-dose female rats. The mean body weight of high-dose males was about 85% of the control value by week 28. By the end of the study, mean body weights of low-, mid-, and high-dose males were 97%, 92%, and 70% of the control values, respectively. Mean body weights of high- and mid-dose females were about 85% of the control values at week 32 and week 44, respectively. At the end of the study, mean body weights of exposed females were about 94%, 81%, and 74% of the control values for low-, mid-, and high-dose groups, respectively. Because of extensive neoplasia, many exposed males and females were dying or were sacrificed moribund in the first year, and all high-dose males died by week 55. The studies were terminated at weeks 60 to 61, at which time the group survivals were male: control, 60/60, low dose, 41/45; mid dose, 50/75; high dose, 0/60; female: 59/60; 39/45; 32/75; 10/60. Nonneoplastic Effects in the 14-Month Studies: Increases in nonneoplastic lesions in dosed rats included cystic degeneration and foci of cellular alteration in the liver; exacerbation of nephropathy; and focal or multifocal hyperplasia of the Zymbal's gland, preputial and clitoral glands, and alveolar epithelium. Neoplastic Effects in the 14-Month Studies: Neoplasms were observed in exposed rats at many sites: skin, Zymbal's gland, preputial and clitoral glands, liver, oral cavity, small and large intestine, mammary gland, lung, brain, and mesothelium. The incidence of these neoplastic effects in male and female rats is summarized in the table at the end of this section (see page 8 of the Technical Report). Genetic Toxicology: 3,3'-Dimethylbenzidine dihydrochloride was mutagenic in Salmonella typhimurium strain TA98 with exogenous metabolic activation; it was not mutagenic in strains TA100, TA1535, or TA97 with or without activation. 3,3'-Dimethylbenzidine dihydrochloride induced sister-chromatid exchanges (CHO) and chromosomal aberrations in CHO cells in the absence of exogenous metabolic activation; these effects were not evident in test with S9 activation. Sex-linked recessive lethal mutations were induced in germ cells of adult male Drosophila melanogaster administered 3,3'-dimethylbenzidine dihydrochloride in feed or by injection. No reciprocal translocations occurred in D. melanogaster germ cells following exposure to 3,3'-dimethylbenzidine dihydrochloride. Conclusions: Under the conditions of these 14-month drinking water studies, there was clear evidence of carcinogenic activity of 3,3'-dimethylbenzidine dihydrochloride for male F344/N rats, as indicated by benign and malignant neoplasms of the skin, Zymbal's gland, preputial gland, liver, oral cavity, small and large intestine, lung, and mesothelium. Increased incidences of neoplasms of the brain may have been related to chemical administration. There was clear evidence of carcinogenic activity for female F344/N rats, as indicated by benign and malignant neoplasms of the skin, Zymbal's gland, clitoral gland, liver, oral cavity, small and large intestine, mammary gland, and lung. Increased incidences of neoplasms of the brain and mononuclear cell leukemia may have been related to chemical administration. Synonyms: o-tolidine dihydrochloride; 3,3'-dimethylbiphenyl-4,4'-diamine dihydrochloride; 3,3'-dimethylbiphenyl-4,4'-biphenyldiamine dihydrochloride; 4,4'-diamino-3,3'-dimethylbiphenyl dihydrochloride

Journal Article↗
PubMed1989

NTP Toxicology and Carcinogenesis Studies of Benzofuran (CAS No. 271-89-6) in F344/N Rats and B6C3F1 Mice (Gavage Studies).

Benzofuran is used as an intermediate in the polymerization of coumarone-indene resins found in various corrosion-resistant coatings such as paints and varnishes, in water-resistant coatings for paper products and fabrics, and in adhesives approved for use in food containers. NTP Toxicology and Carcinogenesis studies were conducted by administering benzofuran (approximately 99% pure) in corn oil by gavage to groups of F344/N rats and B6C3F1 mice of each sex for 14 days, 13 weeks, or 2 years. Genetic toxicology tests were conducted in Salmonella typhimurium, mouse lymphoma cells, and Chinese hamster ovary (CHO) cells. Fourteen-Day Studies: Benzofuran doses for groups of five rats ranged from 63 to 1,000 mg/kg and from 16 to 250 mg/kg for mice. All male and female rats that received 1,000 mg/kg and one female rat that received 500 mg/kg died before the end of the studies. The final mean body weights of male rats that received 250 or 500 mg/kg were 13% or 21% lower than that of controls; the final mean body weight of female rats that received 500 mg/kg was 10% lower than that of controls. Final mean body weights of chemically exposed and control mice were similar. No compound-related histologic lesions were found in rats or mice. Thirteen-Week Studies: Doses for groups of 10 rats and 10 mice ranged from 31 to 500 mg/kg. One female rat that received 500 mg/kg and one that received 250 mg/kg died before the end of the study. Final mean body weights of male rats that received 125, 250, or 500 mg/kg were 11%, 17%, or 27% lower than that of vehicle controls; the final mean body weight of female rats that received 500 mg/kg was 11% lower than that of vehicle controls. Histologic lesions observed in chemically exposed rats included minimal hepatocellular necrosis, increased severity of nephropathy, and cytoplasmic vacuolization of the adrenal cortex. Seven male and three female mice that received 500 mg/kg and one male mouse that received 250 mg/kg died before the end of the 13-week studies. The final mean body weight of mice that received 500 mg/kg was 13% lower than that of vehicle controls. Nephrosis was observed in male mice that received 250 mg/kg. Based on reduced mean body weights, increased severity of nephropathy, and hepatocellular necrosis, benzofuran doses selected for the 2-year studies in rats were 30 or 60 mg/kg for males and 60 or 120 mg/kg for female. Based on increased mortality and nephrosis in male mice, doses selected for the 2-year studies in mice were 60 or 120 mg/kg for males and 120 or 240 mg/kg for females. Body Weights and Survival in the Two-Year Studies: Mean body weights of high dose rats and dosed male mice were 4%-11% lower than those of vehicle controls. Mean body weights of chemically exposed female mice were 8%-35% lower than those of vehicle controls. The survival of chemically exposed male rats was reduced after week 92 (survival at week 89: vehicle control, 47/50; low dose, 39/50; high dose, 38/50; final survival: vehicle control, 33/50; low dose, 12/50; high dose, 18/50). Survival of chemically exposed female rats and male mice was similar to that of vehicle controls after 2 years (female rats: 27/50; 23/50; 25/50; male mice: 33/50; 20/50; 28/50). Deaths of 10 low dose male mice at weeks 20-21 were caused by a dosing error; these animals were not included in survival and tumor analyses. Survival of chemically exposed female mice was reduced after week 89 (final survival: 37/50; 19/50; 21/50). Nonneoplastic and Neoplastic Effects in the Two-Year Studies: Nephropathy occurred with increased severity in chemically exposed male rats. The incidences of parathyroid hyperplasia, fibrous osteodystrophy, mineralization of the pulmonary artery, renal cortical cysts, and hyperplasia of the pelvic epithelium were increased in chemically exposed male rats. The incidence of nephropathy was increased in chemically exposed female rats (vehicle control, 29/50; low dose, 48/50; high dose, 39/50). Renal atypical tubular cell hyperplasia and renal tubular cell adenocarcinomas occurred in chemically exposed femacell hyperplasia and renal tubular cell adenocarcinomas occurred in chemically exposed female rats (atypical tubular cell hyperplasia: 0/50; 1/50; 3/50; tubular cell adenocarcinomas: 0/50; 1/50; 4/50). No renal tubular cell adenocarcinomas have been observed in 2,094 female corn oil vehicle control F344/N rats in National Toxicology Program studies. Chronic inflammation, ulcers, and epithelial hyperplasia of the forestomach were observed at increased incidences in chemically exposed male rats (chronic inflammation: 1/50; 11/50; 6/49; ulcers: 1/50; 5/50; 8/49; epithelial hyperplasia: 9/50; 15/50; 18/49). Metaplastic hepatocytes arising within pancreatic islets occurred at an increased incidence in high dose female rats (0/50; 1/50; 11/49). The incidences of neurilemomas were markedly increased above the historical control incidences (0.1%-0.4%) in all groups of rats (male: 18/50; 13/50; 14/50; female: 7/50; 9/50; 3/50). Syncytial alteration of the liver occurred at increased incidences in male mice exposed to benzofuran. The incidences of hepatocellular adenomas, hepatoblastomas (high dose male mice) and hepatocellular adenomas, hepatocellular carcinomas, or hepatoblastomas (combined) were increased in chemically exposed mice (male--adenomas: 4/49; 24/39; 34/48; hepatoblastomas: 0/49; 3/39; 18/48; carcinomas, adenomas, or hepatoblastomas, combined: 12/49; 31/39; 40/48; female--adenomas: 1/50; 22/48; 21/47; hepatoblastomas: 0/50; 1/48; 2/47; carcinomas, adenomas, or hepatoblastomas, combined: 4/50; 25/48; 22/47). Squamous cell papillomas or carcinomas (combined) of the forestomach were increased in chemically exposed mice (male: 2/49; 11/39; 13/48; female: 2/50; 9/50; 5/50). The incidences of epithelial hyperplasia of the bronchioles were increased in chemically exposed mice. The incidences of alveolar/bronchiolar adenomas or carcinomas (combined) in high dose males and chemically exposed females were increased (adenomas or carcinomas, combined--male: 10/49; 9/39; 19/48; female: 2/50; 9/48; 14/47). Genetic Toxicology: Benzofuran was not mutagenic in S. typhimurium strains TA98, TA100, TA1535, or TA1537 in the presence or absence of exogenous metabolic activation. Benzofuran induced trifluorothymidine resistance in mouse L5178Y lymphoma cells treated in the absence of metabolic activation; this assay was not conducted with activation. Benzofuran induced sister chromatid exchanges but not chromosomal aberrations in CHO cells in the presence and absence of activation. Conclusions: Under the conditions of these 2-year gavage studies, there was no evidence of carcinogenic activity of benzofuran for male F344/N rats receiving doses of 30 or 60 mg/kg per day. There was some evidence of carcinogenic activity of benzofuran for female F344/N rats, based on increased incidences of tubular cell adenocarcinomas of the kidney. There was clear evidence of carcinogenic activity for male and female B6C3F1 mice, based on increased incidences of neoplasms of the liver, lung, and forestomach. Exposure to benzofuran increased the severity of nephropathy in male rats, increased the incidences of nephropathy in female rats, and induced hepatocellular metaplasia in the pancreas in female rats. Nonneoplastic lesions observed in mice exposed to benzofuran included syncytial alteration of the liver, bronchiolar epithelial hyperplasia, and epithelial hyperplasia of the forestomach. Synonyms: coumarone; cumarone

Journal Article↗
PubMed1990

NTP Toxicology and Carcinogenesis Studies of Furfural (CAS No. 98-01-1) in F344/N Rats and B6C3F1 Mice (Gavage Studies).

Furfural is used as a precursor for the manufacture of furan, furfuryl alcohol, tetrahydrofuran, and their derivatives and as an industrial solvent. Furfural is also present in numerous processed food and beverage products. NTP Toxicology and Carcinogenesis studies were conducted by administering furfural (99% pure) in corn oil by gavage to groups of F344/N rats and B6C3F1 mice of each sex for 16 days, 13 weeks, or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, mouse lymphoma cells, Chinese hamster ovary (CHO) cells, Drosophila melanogaster, and mouse bone marrow cells. Sixteen-Day Studies: Rats received doses ranging from 15 to 240 mg/kg, and mice received doses from 25 to 400 mg/kg. Eight of 10 rats that received 240 mg/kg died within 3 days. Final mean body weights of chemically exposed animals were similar to those of vehicle controls; no compound-related histologic lesions were observed in any dosed groups. Thirteen-Week Studies: Rats received doses ranging from 11 to 180 mg/kg, and mice received doses from 75 to 1,200 mg/kg. Most rats that received 180 mg/kg died; mean body weights of chemically exposed rats were similar to those of vehicle controls. Mean relative and absolute liver and kidney weights were increased in male rats that received 90 mg/kg, and cytoplasmic vacuolization of hepatocytes was increased in chemically exposed male rats. Almost all mice that received doses of 600 or 1,200 mg/kg died within the first 3 weeks. Mean body weights of chemically exposed mice were similar to those of vehicle controls throughout the studies. Mean absolute liver weights and liver weight to body weight ratios were increased in females that received 300 mg/kg. Centrilobular coagulative necrosis and/or multifocal subchronic inflammation of the liver were present in chemically exposed mice but not in vehicle control mice. Based on these results, doses selected for the 2-year studies were 0, 30, and 60 mg/kg for rats and 0, 50, 100, and 175 mg/kg for mice. Body Weight and Survival in the Two-Year Studies: Mean body weights of chemically exposed and vehicle control animals were similar throughout the studies for rats and mice. Two-year survival of male rats; low dose female rats, and mice was unaffected by chemical exposure (male rats: vehicle control, 31/50; low dose, 28/50; high dose, 24/50; female rats: 28/50; 32/50; 18/50; male mice: vehicle control, 35/50; low dose, 28/50; mid dose, 24/50; high dose, 27/50; female mice: 33/50; 28/50; 29/50; 32/50). Survival of high dose female rats was reduced by deaths associated with gavage administration; the administration of furfural was considered to be a contributing factor in these gavage-related deaths. Nonneoplastic and Neoplastic Effects in the Two-Year Studies: Centrilobular necrosis of the liver occurred at increased incidences in chemically exposed male rats (vehicle control, 3/50; low dose, 9/50; high dose, 12/50). Two high dose male rats had bile duct dysplasia with fibrosis, and two had cholangiocarcinomas; neither lesion was seen in the other dose groups. The historical incidence of bile duct neoplasms in corn oil vehicle control male rats is 3/2,145 (0.1%). Multifocal pigmentation and chronic inflammation of the subserosa of the liver occurred in chemically exposed mice (pigmentation--male: 0/50; 0/50; 8/49; 18/50; female: 0/50; 0/50; 0/50; 11/50; chronic inflammation--male: 0/50; 0/50; 8/49; 18/50; female: 0/50; 0/50; 1/50; 8/50). The incidences of hepatocellular adenomas and hepatocellular carcinomas in male mice and hepatocellular adenomas in female mice were significantly increased in the high dose group compared with those in the vehicle controls (male--adenomas: 9/50; 13/50; 11/49; 19/50; carcinomas: 7/50; 12/50; 6/49; 21/50; female--adenomas: 1/50; 3/50; 5/50; 8/50; adenomas or carcinomas, combined: 5/50; 3/50; 7/50; 12/50). Three renal cortical adenomas or carcinomas occurred in chemically exposed male mice (0/50; 1/50; 1/49; 1/50), and a renal cortical adenoma was present in one low dose female mouse; the historical incidence oal incidence of renal cortical neoplasms in National Toxicology Program 2-year corn oil gavage studies in male B6C3F1 mice is 8/2,183. Forestomach hyperplasia occurred in chemically exposed female mice, and squamous cell papillomas were increased in high dose female mice (hyperplasia: 0/50; 5/50; 5/50; 3/50; papillomas: 1/50; 0/50; 1/50; 6/50). Genetic Toxicology: In gene mutation tests with four strains of Salmonella (TA98, TA100, TA1535, and TA1537), no mutagenic activity was observed in the presence or absence of exogenous metabolic activation (S9) in one laboratory and an equivocal response was observed in TA100 in the absence of S9 in a second laboratory. Exposure to furfural induced trifluorothymidine resistance in mouse L5178Y lymphoma cells in the absence of S9 (no evaluation was made in the presence of S9), sister chromatid exchanges (SCEs) and chromosomal aberrations in CHO cells in the presence or absence of S9, and an increase in sex-linked recessive lethal mutations but no reciprocal translocations in germ cells of D. melanogaster; furfural did not induce SCEs or chromosomal aberrations in the bone marrow of B6C3F1 mice. Conclusions: Under the conditions of these 2-year gavage studies, there was some evidence of carcinogenic activity of furfural for male F344/N rats based on the occurrence of uncommon cholangiocarcinomas in two animals and bile duct dysplasia with fibrosis in two other animals. There was no evidence of carcinogenic activity for female F344/N rats that received doses of 0, 30, or 60 mg/kg furfural. There was clear evidence of carcinogenic activity for male B6C3F1 mice, based on increased incidences of hepatocellular adenomas and hepatocellular carcinomas. There was some evidence of carcinogenic activity in female B6C3F1 mice, based on increased incidences of hepatocellular adenomas. Renal cortical adenomas or carcinomas in male mice and squamous cell papillomas of the forestomach in female mice may have been related to exposure to furfural. Synonyms: 2-furancarboxaldehyde; 2-furaldehyde; pyromucic aldehyde Common Name: Artificial oil of ants

Journal Article↗
PubMed1989

Toxicology and Carcinogenesis Studies of 4-Vinyl-1-cyclohexene Diepoxide (CAS No. 106-87-6) in F344/N Rats and B6C3F1 Mice (Dermal Studies).

4-Vinyl-1-cyclohexene diepoxide is used a chemical intermediate and as a reactive diluent for diepoxides and epoxy resins. Toxicology and carcinogenesis studies were conducted by administering 4-vinyl-1-cyclohexene diepoxide (97% pure) in acetone by dermal application to individually housed F344/N rats and B6C3F1 mice for 14 days, 13 weeks, 15 months, and 2 years. Additional studies included evaluation of immune function after a 5-day dermal exposure and evaluation of the oral toxicity of 4-vinyl-1-cyclohexene diepoxide in 16-day and 13-week corn oil gavage studies. Genetic toxicology studies were conducted in Salmonella typhimurium, mouse L5178Y lymphoma cells, and Chinese hamster ovary (CHO) cells. Fourteen-Day Dermal Studies: In the 14-day studies, all rats that received 924 mg/kg or higher (equivalent to 139 mg/rat or higher for males and 112 mg/rat of higher for females) died before the end of the studies. Final mean body weights were lower than those of vehicle controls in males receiving 68 mg/rat and in females receiving 57 mg/rat. Excoriations on the skin at the application site were observed in the groups receiving 57 mg/rat or more. Males receiving 139 mg/rat and females receiving 112 mg/rat had congestion and/or hypoplasia of the bone marrow; most had acute nephrosis. Skin lesions, including epidermal necrosis and ulceration, epidermal hyperplasia, and hyperkeratosis, were found in the 139 and 112 mg/rat group; similar lesions of lesser severity were seen in the two lowest dose groups of each sex. All mice that received 1,787 mg/kg (equivalent to 43/mouse for males and 37 mg/mouse for females) and 3/5 male mice and 5/5 female mice that received 889 mg/kg (equivalent to 19-21 mg/mouse) died before the end of the 14-day dermal studies. Final mean body weights of exposed and vehicle control mice were generally similar. Lesions of the skin at the site of application were seen in 4/5 males and 4/5 females receiving 5 mg/mouse and all mice receiving 10 and 21 (males) or 19 (females) mg/mouse and included epidermal and sebaceous gland hyperplasia, hyperkeratosis, and ulceration. Thirteen-Week Studies: In the 13-week dermal studies, all rats survived to the end of the studies (doses up to 60 mg/rat). The final mean body weights of the 60 mg/rat groups were 9%-14% lower than those of the vehicle controls. Compound-related clinical signs in the 60 mg/rat groups observed during the second half of the studies included redness, scabs, and ulceration at the application site and burrowing behavior after dermal application. Hyperplasia of the sebaceous glands and acanthosis (hyperplasia) and hyperkeratosis of the squamous epithelium were seen at the site of application. In mice, no compound-related deaths occurred after applications of up to 10 mg/mouse in 13-week dermal studies, and final mean body weights of exposed and vehicle control mice were similar. Relative liver and kidney weights increased with dose. Compound-related lesions of the skin included sebaceous gland hyperplasia and acanthosis (hyperplasia) and hyperkeratosis of the stratified squamous epithelium at the site of application; ovarian atrophy was also considered to be compound related. In the 13-week oral studies, the major target organ of toxicity in rats and mice was the forestomach, as indicated by hyperkeratosis and hyperplasia of the stratified squamous epithelium. In female mice, ovarian atrophy was seen in 4-vinyl-1-cyclohexene diepoxide-dosed groups. Two-year studies were conducted by administering 4-vinyl-1-cyclohexene diepoxide in acetone by dermal application, 5 days per week for 105 weeks to groups of 60 rats of each sex at 0, 15, or 30 mg/animal. Groups of 60 mice of each sex were administered 0, 2.5, 5, or 10 mg/animal on the same schedule for 103 weeks. None of the doses selected had produced ulceration of skin in 13-week studies. Ten animals from each group were killed and examined during month 15 for toxicologic evaluation. Immune Function Studies: The immunotoxic effects of 4-vinyl-1-cyclohexene diepoxide were studied in male B6C3F1 mice in male B6C3F1 mice after a 5-day dermal exposure at doses ranging from 2.5 to 10 mg/mouse per day. 4-Vinyl-1-cyclohexene diepoxide was immunosuppressive at 10 mg/mouse and, to a lesser extent, at 5 mg/mouse, as indicated by a decrease in peripheral lymphocytes and the in vitro lymphoproliferative response to phytohemagglutinin and concanavalin A in the high dose group and suppression of the antibody plaque-forming-cell response in the 5 and 10 mg/mouse groups. Fifteen-Month Evaluation: Two of 10 male rats that received 30 mg had a squamous cell carcinoma of the skin at or adjacent to the site of application. Acanthosis was seen in exposed rats (mild severity at 30 mg/rat and minimal severity at 15 mg/rat); hyperkeratosis was observed for rats in the 30 mg/rat groups. Compound-related nonneoplastic skin lesions in mice included acanthosis, hyperkeratosis, and sebaceous gland hyperplasia/hypertrophy. Squamous cell papillomas and carcinomas were seen in mice that received 5 or 10 mg/mouse; none was seen in vehicle control or low dose groups (papillomas--male: mid dose, 1/10; high dose, 2/10; female: 1/10; 1/10; carcinomas-- male: 2/10; 8/10; female: 2/10; 5/10). One vehicle control and all exposed female mice had atrophy of the ovary. Hyperplasia of the ovarian surface epithelium was seen in 8/10 females receiving 5 mg/mouse and 9/9 females receiving 10 mg/mouse. Two of nine females receiving 10 mg/mouse had granulosa cell tumors of the ovary, and 1/9 females receiving 10 mg/mouse had an ovarian papillary cystadenoma. Body Weights and Survival in the Two-Year Studies: In general, the body weights and survival were lower in mid and high dose groups than in vehicle controls. The survival was lower in exposed groups, primarily because of neoplasms (survival at week 105--male rats: vehicle control, 7/50; low dose, 8/50; high dose, 4/50; female rats: 27/50; 23/50; 15/50; male mice: vehicle control, 38/50; low dose, 35/50; mid dose, 4/50; high dose, 0/50; female mice: 30/50; 31/50; 15/50; 0/50). All high dose male mice died by week 83; the 10 surviving high dose female mice were killed during week 85. Nonneoplastic and Neoplastic Effects in the Two-Year Studies: Acanthosis and sebaceous gland hypertrophy of skin from the scapula or back were observed at substantially increased incidences in exposed male and female rats. Squamous cell papillomas in male rats and squamous cell carcinomas in male and female rats were observed only in exposed rats (squamous cell carcinomas--male: vehicle control, 0/50; low dose, 33/50; high dose, 36/50; female: 0/50; 16/50; 34/50). The incidences of basal cell adenomas or carcinomas (combined) were increased (male: 0/50; 1/50; 6/50; female: 0/50; 3/50; 4/50). For exposed mice, acanthosis, hyperkeratosis, and necrotizing inflammation of the skin were observed over the scapula or back. Squamous cell carcinomas were found only in exposed mice (male: vehicle control, 0/50; low dose, 14/50; mid dose, 39/50; high dose, 42/50; female: 0/50; 6/50; 37/50; 41/50). Follicular atrophy and tubular hyperplasia of the ovary in female mice were increased (atrophy: 12/50; 43/49; 47/50; tubular hyperplasia: 5/50; 35/49; 38/49; 34/50). Mid and high dose females had benign or malignant granulosa cell tumors (0/50; 0/49; 7/49; 12/50) and benign mixed tumors (0/50; 0/49; 11/49; 6/50). The combined incidences of luteomas, granulosa cell tumors, benign mixed tumors, or malignant granulosa cell tumors in mid and high dose female mice were increased (1/50; 0/49; 17/49; 18/50). The incidences of alveolar/bronchiolar adenomas or carcinomas (combined) in exposed female mice were marginally increased (4/50; 9/50; 11/50; 7/50). Genetic Toxicology: 4-Vinyl-1-cyclohexene diepoxide was mutagenic in S. typhimurium strains TA98, TA100, and TA1535 with and without exogenous metabolic activation; the compound was equivocally mutagenic in strain TA1537 without S9 but gave a positive response in the presence of activation. 4-Vinyl-1-cyclohexene diepoxide induced resistance to trifluorothymidine in mouse L5178Y/TK cells without exogenous metabolic activation; it was not tested with activation. 4-Vinyl-1-cyclohexene diepoxide induced sister chromatid exchanges and chromosomal aberrations in CHO cells in the presence and absence of exogenous metabolic activation. Conclusions: Under the conditions of these 2-year dermal studies, there was clear evidence of carcinogenic activity of 4-vinyl-1-cyclohexene diepoxide for male and female F344/N rats, as shown by squamous cell and basal cell neoplasms of the skin. There was clear evidence of carcinogenic activity of 4-vinyl-1-cyclohexene diepoxide for male and female B6C3F1 mice, as shown by squamous cell carcinomas of the skin in males and squamous cell carcinomas of the skin and ovarian neoplasms in females; increased incidences of lung neoplasms in females may also have been related to chemical application. Synonyms: 4-vinylcyclohexene diepoxide; 4-vinyl-1,2-cyclohexene diepoxide; 1-vinyl-3-cyclohexene diepoxide; 4-vinylcyclohexene dioxide; 1,2-epoxy-4-(epoxyethyl) cyclohexane; 1-epoxyethyl-3,4-epoxycyclohexane

Journal Article↗
PubMed1989

NTP Toxicology and Carcinogenesis Studies of Two Pentachlorophenol Technical-Grade Mixtures (CAS No. 87-86-5) in B6C3F1 Mice (Feed Studies).

Toxicology studies of pentachlorophenol, a biocide used primarily as a wood preservative, were conducted by feeding diets containing a technical-grade composite, Dowicide EC-7 (a technical grade formulation), or pure pentachlorophenol to groups of B6C3F1 mice for 30 days. These three grades plus another commercial grade of pentachlorophenol (DP-2) were used in 6-month studies. These studies were followed by 2-year carcinogenicity studies of technical-grade pentachlorophenol and of Dowicide EC-7 in feed. Genetic toxicology studies were conducted in Salmonella typhimurium and in Chinese hamster ovary (CHO) cells. Thirty-Day and Sixteen-Month Studies: Groups of 19 male mice and 5-15 female mice were fed diets containing 0, 20, 100, 500, 2,500, or 12,500 ppm technical-grade pentachlorophenol, Dowicide EC-7, or pure pentachlorophenol for 30 consecutive days. Necropsies and histopathologic examinations were performed on all animals. Selected organs were weighed. Supplemental analyses included hematology, serum chemistry, urinalysis, immunology, and hepatic enzyme induction. Compound-related deaths were observed at the highest dose (12,500 ppm) with all three materials and at 2,500 ppm with EC-7 and pure pentachlorophenol (males only). Decreases in body weight gain were also observed in the groups in which deaths occurred. Diffuse centrilobular cytomegaly, karyomegaly, nuclear atypia, degeneration, or necrosis of the liver were compound-related lesions observed in all groups that received pure pentachlorophenol, technical-grade pentachlorophenol, or EC-7 at 500 ppm and above. Serum enzymes associated with liver injury were increased. In the 6-month studies, groups of 10 male and 10 female mice were given diets containing the various grades of pentachlorophenol at the following dietary concentrations: 200, 600, or 1,800 ppm technical-grade pentachlorophenol; 200, 600, or 1,200 ppm DP-2 (not used in the 30-day studies); 200, 600, or 1,200 ppm EC-7; or 200, 500, or 1,500 ppm pure pentachlorophenol for 26-27 weeks. Common control groups of 10 male and 10 female mice were fed control diets. Additional groups of male mice were examined for behavioral, histopathologic, clinical pathology, biochemical, and immunologic effects. All mice exposed at the highest dose of technical-grade pentachlorophenol died, as did 2/10 male mice exposed at the highest dose of DP-2. No deaths were observed in mice exposed to EC-7 or pure pentachlorophenol. Markedly lower final body weights were observed in the high dose groups only (all grades of pentachlorophenol). No chemical-relatedclinical signs were observed at sublethal doses. No major behavioral changes were observed after 5 weeks' exposure, but increased motor activity and heightened startle responses were present at the end of the study in female mice exposed to all four grades of pentachlorophenol. All grades of pentachlorophenol caused increases in serum enzymes associated with liver injury. All grades of pentachlorophenol also resulted in a dose-related induction of aryl hydrocarbon hydroxylase and an increase in cytochrome P450. However, the technical grade was a more powerful inducer than the other grades of pentachlorophenol. Pure pentachlorophenol had no effect on humoral or cell-mediated immunity. However, DP-2 and particularly technical-grade pentachlorophenol depressed humoral immune function. A dose-related increase in liver weight was observed in mice exposed to all grades of pentachlorophenol. A dose-related increase in spleen weight was observed in male mice exposed to all grades of pentachlorophenol; a decrease in spleen weight was observed in female mice exposed to all grades of pentachlorophenol except pure. After 6 months' exposure, histopathologic examination consistently revealed effects in the liver and urinary bladder. The liver lesions were present at all doses with all four grades of pentachlorophenol but were less severe at comparable doses in the mice exposed to pure pentachlorophenol; they consisted of hepatocellular karyomegaly, cytomegaly, and degeneration. The changes in the urinary bladder consisted of a brown granular pigment in the cells of the surface epithelium. No inflammation or proliferative response was associated with the pigment. Based primarily on the liver lesions observed in the 6-month studies, diets chosen for the 2-year studies contained 0, 100, or 200 ppm technical-grade pentachlorophenol or 0, 100, 200, or 600 ppm EC-7, fed to groups of 50 male and 50 female mice. DP-2 and pure pentachlorophenol were not chosen for the 2-year studies because of economic considerations and because the clinicopathologic syndrome observed in the 6-month studies was similar to that observed with EC-7. Body Weights and Survival in the Two-Year Studies: Mean body weights of mice exposed to technical-grade pentachlorophenol and EC-7 were comparable to those of controls until weeks 36-82. Thereafter, a 4%-22% dose-related decrease was observed in the mid and high dose mice exposed to EC-7 and in high dose mice exposed totechnical-grade pentachlorophenol. Females were more affected than males. Feed consumption by exposed mice was similar to that by controls. The average daily doses of technical-grade pentachlorophenol were approximately 17-18 or 35 mg/kg compared with 17-18, 34-37, or 114-118 mg/kg of EC-7. Survival of mice did not appear to be affected by exposure to either technical-grade pentachlorophenol or EC-7 at the doses used in these studies. Neoplastic and Nonneoplastic Effects in the Two-Year Studies: The incidences of hepatocellular adenomas and carcinomas were increased (dose related) in male and female mice exposed to either technical-grade pentachlorophenol or EC-7, although the increase was less marked in females exposed to technical-grade pentachlorophenol (adenomas or carcinomas, combined: technical-grade: male-- control, 7/32, 22%; low dose, 26/47, 55%; high dose, 37/48, 77%; female--3/33, 9%; 9/49, 18%; 9/50, 18%; EC-7: male--control, 6/35, 17%; low dose, 19/48, 40%; mid dose, 21/48, 44%; high dose, 34/49, 69%; female-- 1/34, 3%; 4/50, 8%; 6/49, 12%; 31/48, 65%). The incidences of pheochromocytomas in male mice were significantly greater than those in controls for both technical-grade pentachlorophenol (0/31; 10/45, 22%; 23/45, 51%) and EC-7 (1/34, 3%; 4/48, 8%; 21/48, 44%; 45/49, 92%). These neoplasms were also increased in female mice exposed to EC-7 at the highest dose (0/35; 2/49, 4%; 2/46, 4%; 38/49, 78%) but not in those exposed to technical-grade pentachlorophenol (2/33, 6%; 2/48, 4%; 1/49, 2%). Hyperplasia of the adrenal medulla was observed at increased incidences in mice that received either technical-grade pentachlorophenol (male: 1/31; 10/45; female: 0/33; 4/48; 2/49) or EC-7 (male: 1/34; 19/48; 13/48; 1/49; female: 2/35; 1/49; 5/46; 17/49). The incidences of hemangiosarcomas in the spleen and/or liver were significantly greater than those in controls for high dose female mice that received technical-grade pentachlorophenol (0/35; 3/50, 6%; 6/50, 12%) or EC-7 (0/35; 1/50, 2%; 3/50, 6%; 8/49, 16%). Compound-related nonneoplastic lesions occurred in the liver, spleen, and nose in mice exposed to either technical-grade pentachlorophenol or EC-7. The lesions in the liver included dose-related increased incidences of clear cell foci, chronic active inflammation, pigmentation, necrosis, cytomegaly, proliferation of hematopoietic cells, and bile duct hyperplasia. Increased amounts of extramedullary hematopoiesis of the splenic red pulp were observed at increased incidences in dosed male and high dose female mice that received technical-grade pentachlorophenol (male: 5/30; 15/23; 18/46; female: 2/33; 4/13; 11/47). Acutefocal inflammation of the nasal mucosa and focal metaplasia of the olfactory epithelium were observed at increased incidences in high dose mice that received EC-7 (inflammation--male: 4/35; 1/13; 3/16; 47/49; female: 0/35; 0/14; 2/5; 46/48; focal metaplasia-- male: 2/35; 1/13; 2/16; 46/49; female: 1/35; 0/14; 2/5; 45/48) but not in mice exposed to technical-grade pentachlorophenol. Genetic Toxicology: Pentachlorophenol (91.6% pure; equivalent in purity to the technical-grade pentachlorophenol used in the toxicology studies) was not mutagenic in S. typhimurium strains TA98, TA100, TA1535, or TA1537 when tested in the presence or absence of exogenous metabolic activation (S9). In cytogenetic studies with cultured CHO cells, pentachlorophenol produced an increase in chromosomal aberrations in the presence but not the absence of S9 metabolic activation; conversely, sister chromatid exchanges (SCEs) were induced only in the absence of S9. Audit: The data, documents, and pathology materials from the 2-year studies of pentachlorophenol have been audited. The audit findings show that the conduct of the studies is documented adequately and support the data and results given in this Technical Report. Conclusions: Under the conditions of these 2-year feed studies, there was clear evidence of carcinogenic activity for male B6C3F1 mice fed diets containing technical-grade pentachlorophenol, as shown by increased incidences of adrenal medullary and hepatocellular neoplasms. There was some evidence of carcinogenic activity for female B6C3F1 mice exposed to technical-grade pentachlorophenol, as shown by increased incidences of hemangiosarcomas and hepatocellular neoplasms. There was clear evidence of carcinogenic activity for male B6C3F1 mice exposed to pentachlorophenol, EC-7, as shown by increased incidences of adrenal medullary and hepatocellular neoplasms. There was clear evidence of carcinogenic activity for female B6C3F1 mice exposed to pentachlorophenol, EC-7, as shown by increased incidences of adrenal medullary and hepatocellular neoplasms and hemangiosarcomas. Chemically related increased incidences of nonneoplastic lesions in mice of each sex included hepatocellular cytomegaly, necrosis, inflammation, pigmentation, and clear cell foci and intrahepatic bile duct hyperplasia. Synonyms or Common Names: chlorophen; PCP; penchlorol; penta; pentachlorofenol; pentachlorofenolo; pentachlorphenol; 2,3,4,5,6-pentachlorophenol Trade Names: Acutox; Chem-Penta; Chem-Tol; Cryptogil ol; Dowicide 7; Dowicide EC-7; Dow Pentachlorophenol DP-2 Antimicrobial; Durotox; EP 30; Fungifen; Fungol; Glazd Penta; Grundier Arbezol; Lauxtol; Lauxtol A; Liroprem; Moosuran; Pentacon; Penta-Kil; Pentasol; Penwar; Peratox; Permacide; Permagard; Permasan;Permatox; Priltox; Permite; Santophen; Santophen 20; Sinituho; Term-i-Trol; Thompson's Wood Fix; Weedone; Witophen P

Journal Article↗
PubMed2004

NTP technical report on the toxicology and carcinogenesis studies of Elmiron (Cas No. 37319-17-8) in F344/N rats and B6C3F1 mice (Gavage Studies).

UNLABELLED: [structure--see text] Elmiron, a white powder, is the sodium salt of pentosan polysulfate, a semisynthetic sulfated polyanion composed of beta-D-xylopyranose residues with biological properties similar to heparin. Elmiron is used in the United States for the relief of urinary bladder pain associated with interstitial cystitis. Because of its stimulating effect on fibrinolysis, Elmiron has been used clinically in the treatment and prevention of thrombotic disorders. The United States Food and Drug Administration nominated Elmiron for toxicology and carcinogenicity testing by the National Toxicology Program because of its orphan drug status. Male and female F344/N rats and B6C3F1 mice received Elmiron, which met product specifications provided by the manufacturer, in deionized water by gavage for 2 weeks, 3 months, or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, rat and mouse bone marrow cells, and mouse peripheral blood erythrocytes. 2-WEEK STUDY IN RATS: Groups of five male and five female rats were administered 0, 33, 111, 333, 1,000, or 3,000 mg Elmiron/kg body weight in deionized water by gavage, 5 days per week, for 16 days. Elmiron administration had no effect on survival or body weight gain. Activated partial thromboplastin time was significantly increased in 3,000 mg/kg rats. Liver weights of 3,000 mg/kg rats were significantly greater than those of the vehicle controls. Hepatocellular cytoplasmic vacuolization occurred in all 3,000 mg/kg females. 2-WEEK STUDY IN MICE: Groups of five male and five female mice were administered Elmiron in deionized water by gavage at doses of 0, 33, 111, 333, 1,000, or 3,000 mg/kg, 5 days per week, for 16 days. All mice survived to the end of the study. Mean body weight gains of male mice administered 333 mg/kg or greater were significantly greater than that of the vehicle control group. Liver weights of 1,000 and 3,000 mg/kg males were significantly increased. 3-MONTH STUDY IN RATS: Groups of 10 male and 10 female rats were administered Elmiron in deionized water by gavage at doses of 0, 63, 125, 250, 500, or 1,000 mg/kg, 5 days per week, for 14 weeks. No deaths were attributed to administration of Elmiron. Mean body weights of 125 mg/kg males were less than those of vehicle controls and the mean body weights of all dosed groups of females were greater. Hematology results indicated that Elmiron, at the doses selected, induced a minimal erythron decrease and leukocyte and platelet count increases that may have been secondarily related to the inflammatory lesions observed in various tissues of rats. Liver and spleen weights of males administered 250 mg/kg or greater were significantly increased. Liver weights of all dosed groups of females, and kidney, lung, and spleen weights of 1,000 mg/kg females were significantly increased. Histiocytic cellular infiltration, chronic active inflammation, and ulcers of the rectum occurred in most 500 and 1,000 mg/kg rats. Administration of Elmiron was associated with the presence of vacuolated histiocytes in the mandibular and mesenteric lymph nodes, lung, kidney, and liver of male and female rats. Histochemical investigations of the vacuolated histiocytes indicated the presence of neutral and acidic mucins and lipid material within the vacuoles. Transmission electron microscopy identified these vacuoles as lysosomal structures that exhibited a variety of contents. 3-MONTH STUDY IN MICE: Groups of 10 male and 10 female mice were administered Elmiron in deionized water by gavage at doses of 0, 63, 125, 250, 500, or 1,000 mg/kg, 5 days per week, for 14 weeks. One 250 mg/kg female mouse was sacrificed moribund on day 84; all other mice survived to the end of the study. Mean body weights of dosed groups were similar to those of the vehicle control groups. Hematology results indicated that Elmiron, at the doses selected, induced a minimal erythron decrease and leukocyte and platelet count increases that may have been secondarily related to the inflammatory lesions observed in various tissues of mice. in various tissues of mice. Liver weights of 500 mg/kg males and 1,000 mg/kg males and females, and spleen weights of 1,000 mg/kg males were significantly increased. Histiocytic cellular infiltration and chronic active inflammation of the rectum occurred in most 1,000 mg/kg mice. Administration of Elmiron was associated with the presence of vacuolated histiocytes in the mandibular and mesenteric lymph nodes, liver, and spleen of males and females. Histochemical investigations of the vacuolated histiocytes indicated the presence of neutral and acidic mucins within the vacuoles. Transmission electron microscopy identified these vacuoles as lysosomal structures that exhibited a variety of contents. 2-YEAR STUDY IN RATS: Groups of 50 males and 50 females were administered Elmiron in deionized water by gavage at doses of 0, 14, 42, or 126 mg/kg to males and 0, 28, 84, or 252 mg/kg to females, 5 days per week, for 104 or 105 weeks. Survival of all dosed groups of rats was similar to that of the vehicle control groups. Mean body weights of all dosed groups were similar to those of the vehicle controls throughout the 2-year study. Microscopically, myxomatous changes were present in the rectum of 56% of 126 mg/kg males and 83% of 252 mg/kg females. The incidences of chronic active focal alveolar inflammation of the lung were increased in all dosed groups. The incidences of histiocytic cellular infiltration of the mesenteric lymph nodes were increased in 42 and 126 mg/kg males and in 84 and 252 mg/kg females, and lymphohistiocytic hyperplasia was present in the spleen of 126 mg/kg males and 252 mg/kg females. 2-YEAR STUDY IN MICE: Groups of 50 males and 50 females were administered Elmiron in deionized water by gavage at doses of 0, 56, 168, or 504 mg/kg, 5 days per week, for 104 or 105 weeks. Survival of all dosed groups of mice was similar to that of the vehicle control groups. Mean body weights of males were similar to those of vehicle controls. Mean body weights of 504 mg/kg females were progressively less than those of the vehicle controls during the second year of the study. Increased incidences of hemangiosarcomas of the liver and hepatocellular neoplasms were observed in male and female mice. The incidences of hemangiosarcomas in the 504 mg/kg groups exceeded the historical control ranges for males and females; both the trend and the incidence in the 504 mg/kg groups were significant for males. Hemangiosarcomas in males and females were attributed to Elmiron administration. The incidence of hepatocellular adenoma in 504 mg/kg females was significantly increased and exceeded the historical control range; the trends for hepatocellular adenoma and for hepatocellular adenoma or carcinoma (combined) were also significant in females and were attributed to Elmiron administration. There was also a marginal increase in the incidences of hepatocellular neoplasms in male mice, which may have been associated with Elmiron administration. Malignant lymphomas occurred with a positive trend in female mice; the incidence in the 504 mg/kg group was also significantly increased and matched the upper limit of the historical control range. These malignant lymphomas may have been associated with Elmiron administration. Nonneoplastic lesions related to the administration of Elmiron occurred in the liver, rectum, mesenteric lymph node, and spleen of 504 mg/kg mice and to a lesser extent in 168 mg/kg mice. These lesions were similar to those observed in the 3-month study. GENETIC TOXICOLOGY: Elmiron was not mutagenic in S. typhimurium strains TA97, TA98, TA100, or TA1535 with or without induced hamster or rat liver S9 enzymes. No increases in the frequency of micronucleated polychromatic erythrocytes were seen in bone marrow cells of rats or mice administered Elmiron by gavage three times at 24-hour intervals. No significant alterations in the frequency of micronucleated normochromatic erythrocytes were seen in peripheral blood samples from male or female mice administered Elmiron for 3 months by gavage. CONCLUSIONS: Under the conditions of these 2-year gavage studies, there was no evidence of carcinogenic activity of Elmiron in male F344/N rats administered 14, 42, or 126 mg/kg or in female F344/N rats administered 28, 84, or 252 mg/kg. There was some evidence of carcinogenic activity of Elmiron in male B6C3F1 mice based on increased incidences of liver hemangiosarcoma. The increased incidences of hepatocellular neoplasms in male mice may have been related to Elmiron administration. There was some evidence of carcinogenic activity of Elmiron in female B6C3F1 mice based on the increased incidences of liver hemangiosarcoma and hepatocellular neoplasms. The increased incidences of malignant lymphomas in female mice may have been related to Elmiron administration. Elmiron administration caused increased incidences of nonneoplastic lesions (presence of vacuolated histiocytes) of the rectum, lung, mesenteric lymph node, and spleen (males) in rats and of the liver, rectum, mesenteric lymph node, and spleen in mice.

Adenoma, Liver Cell↗
PubMed2004

Results of clinical-toxicological assessments performed in the Poison Control Centre in Zagreb over a 10-year period.

The aim of this study was to see which harmful substances and which occupational settings most often required toxicological assessment, to evaluate exposure data provided by employers and to see to what extent could this assessment rely on actual measurements of harmful substances in a working environment. We reviewed the documentation that was submitted for toxicological assessment in all patients referred from occupational health physicians between 1992 and 2001. From 1992 to 2001, the Poison Control Centre performed a total of 260 toxicological evaluations of occupational exposure to harmful chemicals. In 162 cases (62%), measurements of harmful substance concentrations in the working environment would have been of primary significance for the best comparison of potential adverse effects and the level of exposure. The most frequent was exposure to organic solvents in the production line and the use of various paints and varnishes, adhesives and thinners in shoe, chemical and metal-processing industry. Follows exposure to respiratory irritants, mostly in plastic and metal processing. However, measurement data of harmful substances in the working environment were available only in 24 cases, that is, in 9% of all documents submitted for toxicological assessment. Exposure to organic solvents is characteristic for a large number of work places in industry and small enterprises in Croatia, and it is necessary to carry out a more comprehensive study about the real levels of exposure and modes of effective control. It is important because the EU regulations on the indicative occupational exposure limits (OELs) of harmful substances in the working environment, that will soon be implemented into Croatian legislation, recommend a reduction of maximum allowable concentrations (MAC) for commonly used solvents.

Croatia↗
PubMed2005

Historical blunders: how toxicology got the dose-response relationship half right.

Substantial evidence indicates that reliable examples of hormetic dose responses in the toxicological literature are common and generalizable across biological model, endpoint measured and chemical class. Further evaluation revealed that the hormetic dose response model is more common than the threshold dose response model in objective, head-to-head comparisons. Nonetheless, the field of toxicology made a profound error by rejecting the use of the hormetic dose response model in its teaching, research, risk assessment and regulatory activities over nearly the past century. This paper argues that the hormetic dose response model (formerly called the Arndt-Schulz Law) was rejected principally because of its close historical association with the medical practice of homeopathy as a result of the prolonged and bitter feud between traditional medicine and homeopathy. Opponents of the concept of hormesis, making use of strong appeals to authority, were successful in their misrepresentation of the scientific foundations of hormesis and in their unfair association of it with segments of the homeopathic movement with extreme and discreditable views. These misrepresentations became established and integrated within the pharmacology and toxicology communities as a result of their origins in and continuities with traditional medicine and subsequently profoundly impacted a broad range of governmental risk assessment activities further consolidating the rejection of hormesis. This error of judgment was reinforced by toxicological hazard assessment methods using only high and few doses that were unable to assess hormetic responses, statistical modeling processes that were constrained to deny the possibility of hormetic dose response relationships and by the modest nature of the hormetic stimulatory response itself, which required more rigorous study designs to evaluate possible hormetic responses.

Animals↗
PubMed1991

[Verification of the laboratories based on the program of the control of reliability of toxicological analyses of biological materials 1985-1989].

The evaluation of work of laboratories over the period between 1985 and 1989 is presented made by the Institute of Occupational Medicine in Lódź within the programme of reliability control of toxicological analyses. The analysis made it possible to select all properly working laboratories, as a result of a strict verification. The examination of collected material indicates a need to introduce serious organizational changes in preparing toxicological analyses of biological material. The changes should result in reducing the number of laboratories which perform toxicological analyses and founding several central laboratories active in particular regions of the country. The newly founded centres should participate in the control programmes organized by the Institute of Occupational Medicine in Lódź which would enable the laboratories to get attestation to perform toxicological analyses of biological material.

Certification↗
PubMed1988

Reduction and replacement of laboratory animals in toxicological testing and research. Interim report 1984-1987.

The reasons reduction and replacement of laboratory animals are advancing rapidly in basic biomedical research, and why in industrial toxicology progress is much slower, are analyzed. Reference is made to a previous report from our laboratory, and the general concept of the program is outlined. Encouraging developments concerning acceptance of new concepts in acute toxicity testing by various regulatory agencies are reviewed (OECD, IKS, EEC, and Bureau of Pharmaceutical Affairs, Ministry of Health and Welfare, Japan). On the basis of new concepts proposed by the British Toxicology Society, a program which attempts to evaluate acute toxicity of chemicals as far as possible without causing mortality was started. Continuous in-cage monitoring of motility of animals, regular control of general health, body weight, food and water consumption, and body temperature are used as variables. The possibilities of reducing animal use in toxicology by application of toxicological screening procedures are explained. Screening tests under development include an operant conditioning technique to detect adverse drug interactions with ethanol and a procedure for the detection of nephrotoxic properties. The successful completion of a collaborative program designed to upgrade toxicity testing with contraceptive steroids and to abolish the 7-year beagle and 10-year monkey studies is reported. The application of in vitro cytotoxicity tests for assessment of irritant and corrosive properties of chemicals is discussed and some encouraging progress on regulatory acceptance of such tests (OECD) is reported. A new test developed at the institute is described. An in vitro model for the investigation of chemically induced changes of collagen synthesis in human fibroblasts is presented. Other cell culture methods under development include a culture system of chick brain, retina, and menings cells for the study of neurotoxic chemicals and neurobehavioral teratogens, primary hepatocyte cultures for the study of drug effects on DNA and protein synthesis and ploidy, using flow cytometry, and various in vitro models for the assessment of genotoxic and tumor-promoting activities and malignant cell transformation. The problem of analgesic treatment of animals with chronic pain was investigated. Several analgesics were evaluated, and treatment modalities providing demonstrable analgesia for prolonged periods of time in mice and rats were worked out.

Animal Welfare↗
PubMed1995

Structure activity relationship in toxicology.

One of the basic principles of the modern pharmacological research is that there is a close correlation between the chemical structure and the pharmacological effect. In contrast to pharmacology, in toxicology high doses of the drugs are used in order to provoke toxic symptoms generally realized through other receptors than the pharmacological effect. The evaluation of the structure activity relationship (SAR) in toxicology is hindered by the fact that it is not possible to establish in every case that the toxic effect 1. is developed by the original compound or its metabolite(s) 2. is realized through one or more receptors. Furthermore it is necessary to take into consideration that the studies in toxicology are not carried out with so many compounds as the studies in pharmacology and--horrible dictu--the toxicological data are not always public. Thus the prediction of the toxicity of a compound on the base of its chemical structure is difficult, and the prediction whether a new drug is toxic to such an extent that excludes its development, is impossible. What we can do is trying to predict--in the knowledge of the metabolism of the drug--its possible carcinogenic, hepatotoxic, CNS etc. toxic effect.

Anticonvulsants↗
PubMed1994

Using measures to guide the continuous improvement journey: a partnership between quality assurance and toxicology.

It has been said that you cannot improve what you cannot measure. At Eli Lilly and Company, measurement is one of the five pillars of Total Quality. Quality Assurance and Toxicology have partnered in the use of measures to drive improvements in both areas. Quality Assurance and Toxicology have embarked on a journey in Total Quality to achieve customer satisfaction and drive continuous improvement. Measurement in the research and development world has traditionally not been well received. Contrary to popular belief, we have found that many processes can be measured in the research and development environment. Measurement is critical to the continuous improvement of processes because improvements are made using data. In Quality Assurance and Toxicology, the initial measures were put in place to gather baseline data. As we learned from our measures, we customized them to align with all of our processes. This article describes the journey of measuring Quality Assurance and Toxicology, including highlights of implementation strategies and lessons learned along the way.

Communication↗
PubMed1977

Emergency toxicology in a general hospital.

A study of all cases of attempted suicide by drug ingestion over a 6-month period was undertaken to evaluate the use of an emergency toxicology service and to establish the role of the emergency toxicology laboratory in the diagnosis and management of cases of attempted suicide. A total of 235 requests for emergency toxicologic analysis involving 259 specimens was received. Results of toxicologic screening were positive for 58% of all cases (range, 49% for patients who were drowsy to 90% for patients who were deeply unconscious). Barbiturate blood values did not correlate well with either the level of consciousness or the clinical state of the patient. In almost all patients who were drowsy or who were unconscious but had normal reflexes and vital signs there was no deterioration in the clinical state and no active treatment was required. The study demonstrated the need to educate all personnel involved in the care of patients with attempted suicide to limit laboratory investigations to the management of patients who benefit from such analyses. Quantitative drug analyses have a limited contribution to the management of such patients and should be performed only for patients with mixed drug overdosage and when the drugs require dialysis for their elimination from the body.

Adolescent↗
PubMed1997

Toxicokinetics in the National Toxicology Program.

Toxic responses to test chemicals are known to be dependent on the exposure route, the kinetic behavior of the chemical, and the dose used in the toxicology study. Therefore, knowledge of internal dose is indispensable for the interpretation of toxicology study results, for the facilitation of interspecies scaling, and for risk assessment. By monitoring the blood and/or tissue concentrations of test chemical and/or metabolites versus time after administration of study chemicals by different routes, the bioavailability and kinetic characteristic of test chemicals can be readily obtained. This data can define the so-called linear dose range using area under the plasma concentration versus time curve, clearance, or other related toxicokinetic parameters, and can also be used to predict the possible bioaccumulation under multiple dose regimes. Changes in kinetic parameters after multiple exposures indicate alteration in how the animal handles the chemical (e.g., that there was enzyme induction or inhibition). A recommended approach for conducting toxicokinetic studies generally involves three steps. Step 1 is a preliminary study, which uses a minimum number of animals to estimate the range of blood/tissue concentrations, the required quantitation limit for the analytical method, and the optimal sampling times for the definitive toxicokinetic studies. Step 2 is the definitive study and generates blood and/or tissue concentration data for calculating the toxicokinetic parameters. Step 3 is the toxicokinetic study conducted in conjunction with the toxicology study to determine the internal dose and the effects of age and continuous exposure on kinetic parameters. Examples of the application of NTP toxicokinetic evaluations were also presented in this chapter, demonstrating their use in the design and interpretation of toxicology studies.

Animals↗
PubMed1995

Toxicological data needed for safety evaluation and regulation on inherent plant toxins.

Although the awareness that natural compounds in foodstuffs can have implications for human health is growing, there is a lack of data on the toxicology and occurrence. To enable the safety evaluation of inherent plant toxins adequate toxicological data are necessary. Of most inherent plant toxins at best only limited toxicological data are available, which makes it impossible to perform an accurate safety evaluation. This limited knowledge of inherent plant toxins permits the mystical claim of safety on the basis of history of food use, and thus the development of specific food safety regulation has been postponed. To further develop flexible and adequate regulation, for at least some inherent plant toxins, an adequate set of toxicological data should be available in order to verify and validate the initial regulation. Several problems (e.g., availability of the plant toxin or accuracy of historical human toxicity data) which arise when gathering the necessary data and the development of regulations are discussed and elaborated with a few examples such as solanum alkaloids and glucosinolates. As long as nobody is held responsible to study safety aspects of inherent plant toxins, the lack of data will persist. Therefore a certain level of regulation should be recommended to provide the data needed. Such safety research projects integrated with new agricultural developments should be endorsed by the European Union and other international bodies.

Animals↗
PubMed1990

Prediction of toxicological interactions in a binary mixture by using pattern recognition techniques: proposed approach with a developed model.

A model has been suggested to predict the nature of toxicological interaction in binary mixtures. The approach uses the NLM-HSDB computerized data bases, the ATSDR toxicologic profiles, and other literature for categorizing the nature (synergistic, antagonistic or no interaction) and degree of interaction. Multivariate modeling (pattern recognition techniques) is the statistical approach utilized to separate groups of compounds into those that interact synergistically or antagonistically with a given toxic compound. Preliminary results indicate 1) that there are sufficient data in the literature on interactions to permit such modeling and 2) that in the case of carbon tetrachloride those compounds that interact synergistically with it are more similar to each other than those that interact antagonistically with respect to a number of structural and toxicologic parameters. This suggested approach of utilizing pattern recognition tools will be quite useful for regulatory agencies in predicting toxicological interactions occurring in complex chemical mixtures in the environment.

Carcinogenicity Tests↗
PubMed1991

Toxicological-hygienic requirements for study, registration, and regulations of pesticides in the USSR.

This review discusses the toxicological and hygienic aspects of the extensive increase in pesticide use, which has resulted in the great majority of people throughout the world being affected by their presence. The need for a broad exchange at an international level of the findings of toxicological and hygienic research is established. Brief information on the development of pesticide toxicological research in the USSR is also presented. Accepted criteria for toxicological and hygienic pesticide assessments in the USSR are also systematically reviewed, with respect to the evaluation of physical and chemical properties, toxicity as defined through acute and subacute experiments, cumulative properties, and effects on skin and mucous membranes. The methodology for establishing threshold and noneffective (harmless) levels is also described, along with the prediction of delayed adverse effects. Other areas discussed include the classification of pesticides by degree of toxicity and danger, the system of research and regulation in the USSR, and the principle of integrated standardization of pesticide content of food, water, and atmospheric air. The review concludes with a look at certain prospective trends in the search for and development of pesticides that have selective action on target organisms but are harmless to human health and the environment.

Animals↗