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1.
Regul Toxicol Pharmacol ; 54(3): 272-81, 2009 Aug.
Article in English | MEDLINE | ID: mdl-19460408

ABSTRACT

Eye irritation is an important endpoint in the safety evaluation of consumer products and their ingredients. Several in vitro methods have been developed and are used by different industry sectors to assess eye irritation. One such in vitro method in use for some time already is the isolated chicken eye test (ICE). This investigation focuses on assessing the ICE as a method to determine the eye irritation potential of household cleaning products, both for product safety assurance prior to marketing and for classification and labeling decisions. The ICE involves a single application of test substances onto the cornea of isolated chicken eyes. Endpoints are corneal swelling, corneal opacity and fluorescein retention. The ICE results were compared to historic LVET data in this study due to availability of such in vivo data and the ability to correlate LVET to human experience data on the outcome of accidental exposures to household cleaning products in general. The results of this study indicate that the ICE test is a useful in vitro method for evaluating the eye irritation/corrosion potential and establishing classification and labeling for household cleaning products. For new product formulations, it is best used as part of a weight-of-evidence approach and benchmarked against data from comparable formulations with known eye irritation/corrosion profiles and market experience.


Subject(s)
Animal Testing Alternatives , Detergents/toxicity , Eye Diseases/chemically induced , Irritants/toxicity , Toxicity Tests, Acute/methods , Animals , Chickens , Eye , Female , In Vitro Techniques , Male
3.
Toxicol Lett ; 140-141: 249-59, 2003 Apr 11.
Article in English | MEDLINE | ID: mdl-12676472

ABSTRACT

The objective of this study was to establish the possible occurrence of eye irritation and subjective symptoms in human volunteers exposed to propylene glycol monomethyl ether (PGME) vapour at concentrations of 0, 100 and 150 ppm. Testing was conducted in 12 healthy male volunteers using a repeated measures design. Each subject was exposed for 2.5 h to each of the three exposure conditions that were spaced 7 days apart. The exposure sequences were counterbalanced and the exposure to the test substance and the effect measurements were conducted in a double-blind fashion. During all exposure sessions, 20 ppm diethyl ether was used as a 'masking agent' for vapour exposure. Measurements of pre- and post exposure eye redness, corneal thickness, tear film break-up time, conjunctival epithelial damage, blinking frequency, and subjective ratings on discomfort were used to evaluate the possible irritating effects of PGME. The results indicated no significant treatment effects for any of the objective parameters. Results of the subjective ratings indicated very slight effects on the eyes in the 150 ppm PGME condition only. No significant effects of treatment were found for the remaining questions concerning the perceived intensity of the smell in the room, the (un)pleasantness of the smell, the perceived effects on the skin, effects on the throat, shivering, muscle aching, and intestinal cramps. In conclusion, the results of the present study indicated minimal subjective eye effects at 150 ppm only, and no impact on the objective measures of eye irritation at either of the two exposure levels. It was concluded that the no adverse effect concentration for eye irritation due to PGME vapour was at least 150 ppm.


Subject(s)
Eye Diseases/chemically induced , Eye/drug effects , Irritants/adverse effects , Propylene Glycols/adverse effects , Adult , Double-Blind Method , Eye Diseases/physiopathology , Humans , Male , Propylene Glycols/administration & dosage , Volatilization
4.
Toxicology ; 167(3): 207-15, 2001 Oct 30.
Article in English | MEDLINE | ID: mdl-11578800

ABSTRACT

The guinea pig maximization test (GPMT) has been used as a method for the prediction of skin sensitizing potential for over 30 years. Besides hazard identification, risk assessment of sensitizing chemicals requires the assessment of potency. For the determination of potency based on lowest effective dose levels, dose-response studies are required. In the standard GPMT a single concentration is used for intracutaneous and topical induction and the assay provides a qualitative assessment of allergenicity. This paper presents data derived from quantitative evaluation of the sensitizing potency of chemicals in the GPMT, based on multiple concentrations. We performed the GPMT in accordance with the original procedure of Magnusson and Kligman; and included in this procedure a range of intradermal and topical concentrations for induction. Three allergens with different sensitizing potencies, diethylamine (DEA), tetramethyl thiuram disulfide (TMTD) and zinc dimethyl dithiocarbamate (ZDMC) were tested. The data obtained with this test procedure were compared to data we previously obtained using the local lymph node assay (LLNA). Both the GPMT and the LLNA showed dose response relationships for the three chemicals tested. For the chemicals tested, both tests differed in the relative potencies based on benchmark concentrations. While both tests ranked DEA as the least potent allergen, the GPMT ranked ZDMC more potent than TMTD, the reverse being found in the LLNA. The nature of the data provided in the LLNA makes it likely that benchmarks as defined with this test are more reliable than that defined in the GPMT. However, further validation with human data is necessary.


Subject(s)
Allergens/toxicity , Dermatitis, Allergic Contact/etiology , Local Lymph Node Assay , Animals , Diethylamines/toxicity , Dose-Response Relationship, Immunologic , Edema/chemically induced , Edema/pathology , Erythema/chemically induced , Erythema/pathology , Guinea Pigs , Male , Mice , Skin/drug effects , Skin/pathology , Thiram/toxicity , Time Factors , Ziram/toxicity
5.
J Appl Toxicol ; 21(3): 235-9, 2001.
Article in English | MEDLINE | ID: mdl-11404836

ABSTRACT

In Japan there is growing concern about the possible adverse effects of consumption of food from styrene containers (mainly those made from polystyrene paper) due to the alleged oestrogenic activity of styrene oligomers (dimers and trimers), which may migrate into the food. To examine the possible oestrogenic activity of styrene dimers and trimers, extracts were made from 'general purpose polystyrene (GPPS)' and administered orally to immature female rats over a 4 day period. Increase of uterus weight (wet and blotted) was used for assessment of possible oestrogenic activity. To establish the sensitivity of the test method, immature rats were treated with diethylstilboestrol (DES), a well-known oestrogenic compound. It was found that treatment of rats with levels of up to 60 microg of styrene dimers and 930 microg of styrene trimers per kilogram body weight per day did not give any statistically significant increase of the uterus weight (wet or blotted), whereas DES caused statistically significant, dose-related increases in uterus weight at levels as low as 0.89 microg kg(-1) body weight day(-1). It was concluded that, compared with the estimated maximum human daily intake of styrene trimers of 1 microg kg(-1) body weight day(-1) from polystyrene food containers, the risk of adverse human health effects with respect to oestrogenicity may be considered negligible.


Subject(s)
Polystyrenes/adverse effects , Uterus/drug effects , Administration, Oral , Animals , Dose-Response Relationship, Drug , Estrogens/pharmacology , Female , Food Contamination , Humans , Hypertrophy , Public Health , Rats , Rats, Wistar , Uterus/anatomy & histology
6.
Altern Lab Anim ; 27(1): 53-77, 1999.
Article in English | MEDLINE | ID: mdl-25423402

ABSTRACT

This is the report of the thirty-fourth of a series of workshops organised by the European Centre for the Validation of Alternative Methods (ECVAM). ECVAM's main goal, as defined in 1993 by its Scientific Advisory Committee, is to promote the scientific and regulatory acceptance of alternative methods which are of importance to the biosciences and which reduce, refine or replace the use of laboratory animals. One of the first priorities set by ECVAM was the implementation of procedures which would enable it to become well-informed about the state-of-the-art of non-animal test development and validation, and the potential for the possible incorporation of alternative tests into regulatory procedures. It was decided that this would be best achieved by the organisation of ECVAM workshops on specific topics, at which small groups of invited experts would review the current status of various types of in vitro tests and their potential uses, and make recommendations about the best ways forward (1). The workshop on Eye Irritation Testing: The Way Forward was held in Egham, UK, on 15-17 June 1998, under the chairmanship of Michael Balls (ECVAM, Italy). The workshop had two aims, the first of which was to review some of the previous multi-laboratory validation studies on alternatives to the Draize eye test and assess why many promising alternative methods were not successful in these studies. The second aim was to discuss strategies for making progress toward the short-term reduction, refinement, and eventual replacement, of the Draize test, including: a new approach to the validation of in vitro tests for eye irritancy, based on the use of reference standards, which promises to overcome some of the problems encountered in previous studies; the use of stepwise testing strategies which reduce and refine the use of animals in eye irritation testing; the use of multivariate and other statistical techniques for the further analysis of data generated in previous validation studies; and a programme of research aimed at understanding the underlying mechanisms of eye irritation.

7.
Food Chem Toxicol ; 35(9): 923-6, 1997 Sep.
Article in English | MEDLINE | ID: mdl-9409633

ABSTRACT

The guinea pig maximization test is one of the preferred test methods for the identification of skin sensitizers. The OECD/EC test guidelines allow for the conduct of a rechallenge in case doubtful reactions are obtained after challenge. The relevance of rechallenging was investigated by performing multiple challenges (up to four) in the maximization test with four well-known sensitizers of varying strength: nickel sulfate, sulfathiazole, benzocaine, and 1-chloro-2,4-dinitrobenzene. In addition, the effect of sodium lauryl sulfate (SLS)-pretreatment during topical induction with weak sensitizers on rechallenging was investigated. In contrast to what has frequently been hypothesized, rechallenge did not result in an increase of skin reaction as compared with the reactions observed after the first treatment. SLS pretreatment was very effective in increasing the initial challenge response to weak sensitizers. Subsequent rechallenging in these cases however again showed a decrease in sensitivity of the animals.


Subject(s)
Skin/drug effects , Sodium Dodecyl Sulfate/toxicity , Animals , Benzocaine/toxicity , Dinitrochlorobenzene/toxicity , Female , Guinea Pigs , Irritants/toxicity , Male , Nickel/toxicity , Sulfathiazole , Sulfathiazoles/toxicity
8.
Food Chem Toxicol ; 35(3-4): 337-48, 1997.
Article in English | MEDLINE | ID: mdl-9207896

ABSTRACT

The acute and subacute toxicity of five biogenic amines-tyramine, spermidine, spermine, putrescine and cadaverine-were examined in Wistar rats. Tyramine and cadaverine had a low acute oral toxicity of more than 2000 mg/kg body weight. Putrescine had an acute oral toxicity of 2000 mg/kg body weight and spermidine and spermine each of 600 mg/kg body weight. All amines investigated caused a dose-related decrease in blood pressure after intravenous administration, except for tyramine, where an increase was found. In 6-wk studies the biogenic amines were administered in the diet to groups of 10 male and 10 female rats. Tyramine and cadaverine were given at levels of 0, 200, 2000 or 10,000 ppm, spermine and putrescine at levels of 0, 200, 2000 or 5000 ppm and spermidine at levels of 0, 20, 200 or 500/1000 ppm in the first study and at levels of 0 or 10,000 ppm in a second study. Spermine was the most toxic. The high dose level showed a great number of changes, such as emaciation, aggressiveness, convulsions and paralysis of the hind legs. Growth, food intake and water intake were considerably decreased. Slight anaemia (males) and changes in plasma clinical chemistry occurred. The relative weights of the thyroid, adrenals, spleen and heart were increased and that of the liver decreased. Impaired kidney function, together with renal histopathological changes and changes in plasma electrolytes and urea, occurred with spermine. Histopathological examinations also revealed decreased glycogen content in the liver, reduction of spermatogenesis, severe depletion of splenic white pulp, acute involution of the thymus and moderate myocardial degeneration in the heart. Myocardial degeneration was also seen in one mid-dose male. Adverse effects were also observed in the top dose groups of all other amines. Decreased body weights associated with diminished food intake were generally seen. Slight increases in packed cell volume, haemoglobin concentration and thrombocytes occurred with cadaverine. With spermidine, decreased plasma creatinine, calcium and inorganic phosphate were observed and decreased potassium levels with cadaverine. The no-observed-adverse-effect level was 2000 ppm (180 mg/kg body weight/day) for tyramine, cadaverine and putrescine, 1000 ppm (83 mg/kg body weight/day) for spermidine and 200 ppm (19 mg/kg body weight/day) for spermine.


Subject(s)
Biogenic Monoamines/toxicity , Administration, Oral , Animals , Blood Pressure/drug effects , Body Weight/drug effects , Chemistry, Clinical , Drinking/drug effects , Eating/drug effects , Female , Hematologic Tests , Injections, Intravenous , Lethal Dose 50 , Male , No-Observed-Adverse-Effect Level , Organ Size/drug effects , Rats , Rats, Wistar , Survival Rate
9.
Food Chem Toxicol ; 35(1): 23-37, 1997 Jan.
Article in English | MEDLINE | ID: mdl-9100813

ABSTRACT

The brief of the Organotypic Models Working Group was to review data submitted to the Interagency Regulatory Alternatives Group on the use of isolated eyes and components of the eye used to predict eye irritation potential. Data submissions were received on four test systems: the isolated rabbit eye (one submission), the isolated chicken eye (one submission), the bovine cornea (eight submissions) and the cultured bovine lens (one submission). On the basis of the data submitted on each test it was concluded that the isolated rabbit eye test as performed was capable of screening for severe eye irritants, but overall was of no practical value for determining irritation potential across the full range; that the isolated chicken eye test as performed showed promise as a method of predicting eye irritation potential, but the database was too small and needed expanding; that the bovine corneal opacity test had an extensive database and overall performed reasonably at screening out severe irritants and performed well for assigning relative potencies; and that the bovine lens test should be researched further to demonstrate its utility. The overall conclusion drawn was that the isolated eye tests and the bovine corneal opacity test can be used now to screen for severely irritating materials. However, it would be unwise to rely solely on these organotypic methods to provide evidence of lack of eye irritation hazard.


Subject(s)
Eye Diseases/chemically induced , Eye/drug effects , Irritants/toxicity , Animal Testing Alternatives/methods , Animals , Cattle , Cells, Cultured , Chickens , Cornea/drug effects , Cornea/pathology , Cornea/physiopathology , Corneal Opacity/chemically induced , Eye/pathology , Eye Diseases/pathology , In Vitro Techniques , Lens, Crystalline/cytology , Lens, Crystalline/drug effects , Permeability/drug effects , Predictive Value of Tests , Rabbits , Toxicity Tests/methods
10.
Food Chem Toxicol ; 34(3): 291-6, 1996 Mar.
Article in English | MEDLINE | ID: mdl-8621111

ABSTRACT

The enucleated eye test with chicken eyes (CEET) obtained from an abattoir proved to be a valuable and practical alternative for the 'traditional' enucleated eye test with eyes of laboratory rabbits. Since 1992, the CEET has been incorporated in standard contract toxicity testing at the Toxicology Division of the TNO Nutrition and Food Research Institute as a (pre)screen for the Draize eye test with rabbits. The results of the first 44 compounds tested showed excellent correlation with the in vivo results. The CEET identified non-irritating or severely irritating compounds, and predicted (slightly to moderately) irritating compounds. Statistical analysis of the CEET and the rabbit in vivo scores showed high linear correlations between the critical values of both tests and confirmed the relevance of this assay with respect to ocular effects. In general, tiered in vitro/in vivo testing was considered a meaningful approach for further validation of alternative methods and for reducing the use of suffering of laboratory animals to a minimum. Tiered testing of compounds in cases of eye irritation hazard assessment should be incorporated in the legislation of the European Community.


Subject(s)
Eye Enucleation , Irritants/toxicity , Toxicity Tests/methods , Animal Testing Alternatives , Animals , Chickens , Cornea/drug effects , Corneal Opacity/chemically induced , Drug Evaluation, Preclinical , Epithelium/drug effects , In Vitro Techniques , Rabbits
11.
Toxicol In Vitro ; 9(6): 857-62, 1995 Dec.
Article in English | MEDLINE | ID: mdl-20650167

ABSTRACT

With regard to the problems encountered and the experience gained in validation studies conducted in the past, suggestions have been made concerning criteria for the selection of the tests and laboratories to be included in a validation study, the selection and distribution of test chemicals, and procedures for the handling, analysis and interpretation of the resulting data. In particular, tests should have been developed to the extent that detailed protocols and standard operating procedures have been produced and evaluated. The laboratories should be chosen on the basis of evidence of their appropriate experience, competence and ability to comply with good laboratory practice (GLP) requirements. The choice of test chemicals depends primarily on the goals of the validation study and on the availability of reliable in vivo toxicity data of high quality. A biostatistician should be involved in the initial design of the validation study as well as in the analysis of the resulting data. The quality of the in vivo and in vitro data must be ensured, prior to determining the reproducibility and predictivity of the alternative test.

12.
Food Chem Toxicol ; 31(1): 69-76, 1993 Jan.
Article in English | MEDLINE | ID: mdl-8444390

ABSTRACT

The enucleated eye test (EET) with the isolated eye of rabbits has been recognized as a valuable alternative to the Draize test, because it represents a test system nearest to the in vivo test, without the need to use live animals. In this ex vivo bioassay, three parameters are measured to detect possible adverse eye effects, namely corneal swelling, corneal opacity and fluorescein retention. The measurement of corneal swelling in this assay guarantees a highly objective and discriminative parameter. In combination with the detailed observation of corneal opacity and fluorescein retention, a reliable evaluation of the eye irritation potential of test materials is achieved. However, laboratory animals are still necessary as eye donors. The use of slaughter animals, such as the cow, the pig and the chicken, as possible as eye donors for the EET was therefore examined. From these candidates, the chicken appeared to be the most practicable. 21 reference compounds, ranging from non-irritant to severe irritant, which had been tested previously in a validation study on alternative test methods for eye irritation testing, sponsored by the Commission of the European Communities, were examined in the Chicken Enucleated Eye Test (CEET). When compared with the in vivo EC classification, the CEET correctly classified each of the compounds that must be labelled in the EC as irritant (R36) or severely irritant (R41). In addition, since the CEET recognizes three levels of irritancy rather than two (as in the case of the EC classification) a small number of the compounds were recognized as slightly irritant, which according to the EC classification need not be labelled. It was concluded that this ex vivo test system is highly accurate in the assessment of eye irritation potential without the use of laboratory animals.


Subject(s)
Animal Testing Alternatives , Eye Diseases/chemically induced , Eye Enucleation , Animals , Cattle , Chickens , Cornea/pathology , Eye Diseases/metabolism , Eye Diseases/pathology , Fluorescein , Fluoresceins/metabolism , Fluorescent Dyes , Rabbits , Species Specificity , Swine
13.
Carcinogenesis ; 13(4): 669-74, 1992 Apr.
Article in English | MEDLINE | ID: mdl-1533574

ABSTRACT

The purpose of this study was to determine the carcinogenic effect in male rats of a single i.v. injection of N-methyl-N-nitrosourea (MNU) after sequential treatment with cyproterone acetate (for 21 days) and testosterone propionate (for 3 days). This treatment has previously been shown to induce carcinomas of the prostate and other male accessory sex glands. A wide spectrum of non-melanoma skin tumors was found in 38-48% of Wistar (Cpb:WU) rats given this sequential treatment, but only in 5% of rats that received only MNU. Castration long and, particularly, early after MNU markedly reduced this skin tumor response to a 10-13% incidence. The skin tumorigenic efficacy of MNU was dependent on the time between the start of the testosterone propionate treatment and carcinogen administration: MNU injection after 48-50 or 60-63 h induced skin tumors in 17-21% of Wistar rats, whereas injection after 72-74 h induced a 48% incidence. The Fischer F344 and Sprague-Dawley strains were not very sensitive to induction of skin tumors by this approach. Thyroid follicular cell tumors were also induced by MNU only after the hormonal pretreatment, and their induction was influenced by the time of MNU injection as well. The time of MNU injection and rat strain used did not significantly influence the induction of sebaceous-squamous neoplasms of the ear-duct/Zymbal's glands or other tumors. These data indicate that endogenous androgens are critically involved in the later stages of rat skin tumorigenesis and suggest that androgen-induced cell proliferation influences the initiation stage of this process and, possibly, of thyroid tumorigenesis.


Subject(s)
Cyproterone/analogs & derivatives , Methylnitrosourea/toxicity , Skin Neoplasms/chemically induced , Testosterone/toxicity , Thyroid Neoplasms/chemically induced , Animals , Cyproterone/toxicity , Cyproterone Acetate , Male , Orchiectomy , Rats , Rats, Inbred Strains , Species Specificity , Time Factors
14.
Prostate ; 20(4): 339-53, 1992.
Article in English | MEDLINE | ID: mdl-1535126

ABSTRACT

Wistar (Cpb:WU), F344 or Sprague-Dawley rats were sequentially treated with cyproterone acetate (CA) for 21 days, testosterone propionate (TP) for 3 days, followed by a single i.v. injection of N-methyl-N-nitrosourea (MNU). One group of Wistar rats was castrated 4 weeks after MNU injection, and another group 58 weeks after MNU, when the first prostatic carcinoma was detected. Control groups received only CA + TP, CA, MNU, or they remained untreated. Early or late castration inhibited the development of atypical hyperplasia of the ventral prostate in Wistar rats. This lesion was induced by the CA + TP + MNU treatment in F344 rats, but not Sprague-Dawley rats; in Wistar rats, it was induced by CA + TP treatment, irrespective of whether MNU was given. Hypertrophic-hyperplastic lesions of the seminal vesicle were induced by MNU, irrespective of pretreatment, and their development was prevented by early castration and inhibited by late orchiectomy. Dorsolateral prostate carcinomas and preneoplasia occurred only in low incidence in Wistar and Sprague-Dawley rats. These lesions were absent in F344 rats that had received treatment with CA + TP + MNU. No dorsolateral prostate (pre)neoplasia was found in Wistar rats subjected to early orchiectomy, but rats castrated at 58 weeks had an incidence similar to that for the intact group treated with CA + TP + MNU. This finding supports the contention that androgens are required for the development of MNU-induced prostatic cancer in rats but that advanced carcinomas are androgen insensitive. Differences in incidence and localization of prostatic proliferative lesions between F344 and Wistar rats and between dorsolateral and ventral prostate could not be explained by differences in epithelial cell proliferative responses to CA + TP treatment at the time of MNU injection, since they were similar in ventral and dorsolateral prostate and were more prominent in F344 rats than in Wistar rats. DNA damage as estimated by MNU-induced unscheduled DNA synthesis also did not differ between dorsolateral and ventral prostate.


Subject(s)
Cyproterone/analogs & derivatives , Genital Neoplasms, Male/chemically induced , Methylnitrosourea , Orchiectomy , Prostatic Neoplasms/chemically induced , Rats, Inbred Strains/physiology , Seminal Vesicles/drug effects , Testis/physiology , Testosterone/pharmacology , Androgens/physiology , Animals , Cyproterone/pharmacology , Cyproterone Acetate , DNA Replication/drug effects , DNA, Neoplasm/biosynthesis , Male , Rats , Rats, Inbred F344 , Seminal Vesicles/pathology , Time Factors
15.
Cancer Res ; 50(3): 691-9, 1990 Feb 01.
Article in English | MEDLINE | ID: mdl-2137026

ABSTRACT

Groups of 20-25 male Wistar rats (Cpb:WU), nine groups of 4-week-old rats, and nine groups of 8-week-old rats, were given cyproterone acetate (CA) s.c. or by gavage daily for 18 days at a dose of 50 mg/kg/day. Directly following CA treatment, the rats received 3 daily s.c. injections with testosterone propionate (TP) at a dose of 100 mg/kg/day. On the day after the last TP administration, a single dose of one of the following carcinogens was given to 3 groups: N-methyl-N-nitrosourea (MNU), 50 mg/kg i.v.; 7,12-dimethylbenz(a)anthracene, 30 mg/kg i.v.; 3,2'-dimethyl-4-aminobiphenyl, 250 mg/kg s.c. Three other groups received the same carcinogen treatments after 7 days of recovery from the CA administration. The last 3 groups received carcinogen without TP treatment, but immediately after CA pretreatment was stopped. A 25% incidence of invasively growing, metastasizing adenocarcinomas was found in the dorsolateral prostate region of 8-week-old rats that had received MNU after treatment with CA plus TP. In addition, this group had a 5% incidence of carcinoma in situ and a 5% incidence of atypical hyperplasia in the dorsolateral prostate. Lower incidences of adenocarcinoma of the dorsolateral prostate region and of carcinoma in situ and atypical hyperplasia of the dorsolateral prostate were found in other groups that were treated with MNU or 7,12-dimethylbenz(a)anthracene after pretreatment with CA, followed by TP or recovery, but never in rats that had been treated with CA only. In the groups treated with 3,2'-dimethyl-4-aminobiphenyl, which is slowly metabolized, these lesions were also found in groups that were pretreated with only CA. The carcinomas seemed to originate from the dorsolateral prostate and their average latency time was approximately 61 weeks. The 8-week-old rat given a MNU injection after sequential treatment with CA and TP may provide a relevant animal model for human prostatic cancer.


Subject(s)
9,10-Dimethyl-1,2-benzanthracene/administration & dosage , Adenocarcinoma/chemically induced , Aminobiphenyl Compounds/administration & dosage , Cyproterone/analogs & derivatives , Methylnitrosourea/administration & dosage , Prostatic Neoplasms/chemically induced , Testosterone/administration & dosage , Animals , Body Weight/drug effects , Cyproterone/administration & dosage , Cyproterone Acetate , Genitalia, Male/anatomy & histology , Male , Rats , Rats, Inbred Strains , Sarcoma, Experimental/chemically induced , Survival Analysis
16.
Cancer Res ; 50(3): 700-9, 1990 Feb 01.
Article in English | MEDLINE | ID: mdl-2105161

ABSTRACT

Carcinomas of the rat prostate induced by a single injection of N-methyl-N-nitrosourea, 7,12-dimethylbenz(a)anthracene, and 3,2'-dimethyl-4-aminobiphenyl, after sequential treatment with cyproterone acetate and testosterone propionate, were evaluated as potential animal models for prostatic cancer. All ten carcinomas examined were located in the dorsolateral prostate region and did not involve the distal parts of the seminal vesicles and coagulating glands. The incidence of urinary obstruction leading to the animals' death was 6 of 10 rats, and metastases in the lung, abdominal lymph nodes, and/or liver also occurred in 6 of 10 rats. The tumors were invasive adenocarcinomas, showing frequent perineural invasion and a variable degree of differentiation. There were ultrastructural similarities with human prostatic carcinomas, such as intracellular lumina. Plasma acid phosphatase was increased. Enzyme histochemical analysis revealed similarities with the Dunning R3327H and -HI prostatic carcinomas but was not helpful in determining the site of origin of the tumors. The gross and microscopic appearance of the tumors and the observation of preneoplastic lesions exclusively located in the dorsolateral prostate suggest this lobe as site of origin of the carcinomas. Preneoplastic lesions (n = 9) included atypical hyperplasias (n = 5) and lesions with all histological characteristics of carcinoma except for local invasion and metastases, which were classified as carcinoma in situ (n = 4). Although androgen sensitivity could not be assessed, the observed characteristics of the tumors [their long latency time (46-80 weeks), the presence of preneoplastic lesions, and the short duration of the treatment, leaving the animals intact] all indicate that the present approach is a valid animal model for the study of prostatic carcinogenesis.


Subject(s)
Adenocarcinoma/pathology , Prostatic Neoplasms/pathology , 9,10-Dimethyl-1,2-benzanthracene , Acid Phosphatase/blood , Adenocarcinoma/enzymology , Aminobiphenyl Compounds , Animals , Carcinoma in Situ/enzymology , Carcinoma in Situ/pathology , Cell Differentiation , Histocytochemistry , Hyperplasia/pathology , Male , Methylnitrosourea , Microscopy, Electron , Neoplasm Metastasis , Precancerous Conditions/enzymology , Precancerous Conditions/pathology , Prostatic Neoplasms/enzymology , Rats
17.
Cancer Lett ; 18(1): 69-78, 1983 Feb.
Article in English | MEDLINE | ID: mdl-6218869

ABSTRACT

Prostatic adenocarcinomas were induced in 5 out of 20 Wistar rats upon a single administration of 50 mg/kg N-nitroso-N-methylurea (NMU). The rats were pretreated with a daily dose of 50 mg/kg cyproterone acetate for 3 weeks followed by 3 daily injections of 100 mg/kg testosterone. All tumours developed in the dorsolateral prostate and were invasively growing. In 2 cases distant metastases were found. Three proliferative lesions classified as carcinomas in situ were also found in the dorsolateral prostate. A total of 7/20 animals (35%) carried an adenocarcinoma and/or a carcinoma in situ. In addition, 6 epithelial hyperplasias were observed in the dorsolateral and 1 in the ventral prostate of non-tumour-bearing rats. The method described may provide a good animal model for cancer of the prostate and lead to a better understanding of prostatic carcinogenesis.


Subject(s)
Adenocarcinoma/chemically induced , Carcinoma in Situ/chemically induced , Cyproterone/analogs & derivatives , Methylnitrosourea , Nitrosourea Compounds , Prostatic Neoplasms/chemically induced , Testosterone/pharmacology , Animals , Cocarcinogenesis , Cyproterone/pharmacology , Cyproterone Acetate , Male , Models, Biological , Neoplasm Metastasis , Neoplasms, Experimental/chemically induced , Rats , Rats, Inbred Strains
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