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Dit proefschrift beschrijft de ontwikkeling, optimalisatie, validatie (binnen TNO) en toepassing van een alternatieve test met geïsoleerde ogen van kippen (de Isolated Chicken Eye, kortweg de ICE test) en in bredere zin de internationale validatie en acceptatie van de ICE test door overheidsinstanties.

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. © 2003 Elsevier Science Ireland Ltd. All rights reserved.

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. © 2001 Elsevier Science Ireland Ltd. All rights reserved. Chemicals/CAS: Allergens; diethylamine, 109-89-7; Diethylamines; Thiram, 137-26-8; Ziram, 137-30-4

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 μg of styrene dimers and 930 μg 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 μg kg-1 body weight day-1. It was concluded that, compared with the estimated maximum human daily intake of styrene trimers of 1 μg 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. Copyright © 2001 John Wiley & Sons, Ltd. Chemicals/CAS: Estrogens; Polystyrenes

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 ye 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.

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. Chemicals/CAS: Irritants

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 model for prostatic cancer. All ten carcinomas examined were located in the dorsolateral prostate region and did not involve the distal parts of the seminal vesicle 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 carcinoas, such as intracellular lumina. Plama 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 or 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 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. Chemicals/CAS: cyproterone acetate, 427-51-0; testosterone propionate, 57-85-2; 2',3-dimethyl-4-aminobiphenyl, 13394-86-0; 9,10-Dimethyl-1,2-benzanthracene, 57-97-6; Acid Phosphatase, EC 3.1.3.2; Aminobiphenyl Compounds; Methylnitrosourea, 684-93-5

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. Chemicals/CAS: cyproterone acetate, 427-51-0; methylnitrosourea, 684-93-5; testosterone propionate, 57-85-2; testosterone, 58-22-0; Cyproterone Acetate, 427-51-0; Cyproterone, 2098-66-0; Methylnitrosourea, 684-93-5; Nitrosourea Compounds; Testosterone, 57-85-2