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Toxicity data of 82 compounds, tested in both a sub-acute and a sub-chronic study, were evaluated to find out whether it is possible to substitute a sub-acute for a sub-chronic study without losing quantitative information. The no-effect level (NEL) and the minimal-effect level (MEL) were used as the basis for comparison. For each of the compounds, the sub-acute and sub-chronic studies were performed under similar conditions, with the same strain of rats and with a comparable range of dietary levels. It appeared that the NEL in the sub-acute study was equal to the NEL in the sub-chronic study for 56% of the compounds. For 44% of the compounds reviewed, the NEL in the sub-chronic test was lower than the NEL in the sub-acute test, indicating that a sub-chronic study cannot simply be replaced by a sub-acute study. However, it may be acceptable to use the NEL obtained in a sub-acute study as a basis for establishing acceptable daily intakes or permissible exposure levels for humans if an additional safety factor of 10 is applied. Furthermore, it was concluded that the conventional sub-acute study, including some selected haematological and biochemical parameters, seems extremely useful to obtain quick and reliable information on the toxicity of the numerous non-regulated chemicals which have to be investigated in the years to come.

Despite increasing standardisation and international harmonisation of the long-term carcinogenicity study in rodents there are still areas of controversy such as high-dose selection, duration of the test period, combining or not combining the chronic toxicity and the carcinogenicity study, the use of historical control data, conditions for redundancy of the study, and significance of studies of restricted design. It is discussed that the 'Maximum Tolerated Dose', or doses above and below the 'metabolic break-point' should be included. In general a test period of 24 months is adequate, but the protocol should be flexible enough to allow extension beyond 24 months. Major advantages of the combined chronic toxicity/carcinogenicity study are that the toxicity and carcinogenicity data are obtained with the same sample of the test compound using the same batch of animals kept on the same diet under the same environmental conditions. It is discussed that the use of historical control data will not lead to a final conclusion on carcinogenic or noncarcinogenic potential of a compound. A long-term carcinogenicity study is considered reduntant (a) when adequate (semi-chronic) toxicity studies including reproduction and mutagenicity tests and pre-screens for carcinogenicity, do not indicate mutagenic or carcinogenic activity, and (b) when there is a wide margin (e.g. 1000) between the 'no-observed-adverse effect level' and the (presumed) exposure level in humans. Studies of restricted design and conduct may clearly demonstrate carcinogenicity but also may easily lead to inconclusive results.

To study the significance of damage to the nasal mucosa for the induction of nasal tumours by formaldehyde in rats, a long-term inhalation study was conducted in which male rats with severely damaged or undamaged nose were exposed 6 h/day for 5 days/week to 0, 0.1, 1.0 or 10 ppm formaldehyde vapour for 28 months, or for 3 months followed by a 25-month observation period. The damage to the nasal mucosa was induced by bilateral intranasal electrocoagulation. The total number of rats used was 720, 480 with damaged and 240 with intact nose. Compound-related degenerative, inflammatory and hyperplastic changes of the nasal respiratory and olfactory mucosa were invariably observed when rats with intact nose were exposed to 10 ppm but not when exposed to 1.0 or 0.1 ppm formaldehyde. Nasal electrocoagulation increased the incidences of formaldehydeinduced rhinitis, hyper- and metaplasia of the respiratory epithelium, and degeneration and hyper- and metaplasia of the olfactory epithelium. In addition, exposure to 10 ppm formaldehyde for 28 months produced nasal squamous cell carcinomas in rats with damaged nose (15/58) but not in rats with intact nose. Three months of exposure to 10 ppm formaldehyde or exposure to 0.1 or 1.0 ppm formaldehyde for 28 months had no such effect. It was concluded that severe damage to the nasal mucosa may contribute to the induction of nasal tumours by formaldehyde.

The effects of exposure pattern on the toxicity of acetaldehyde vapour were investigated in 4-week inhalation studies. Male rats were exposed to 500 or 150 and 110 ppm for 6 h per day/5 days per week. One group of animals was exposed without interruption, the exposure of a second group was interrupted for 1.5 h between the first and second 3-h periods, the exposure of a third group was similarly interrupted and for six 5 min periods exposure was increased sixfold. Peak exposures of up to 3000 ppm superimposed on 500 ppm acetaldehyde caused irritation and excitation, and reduced body weight gain. No such effects occurred after interrupted or uninterrupted exposure to 500 ppm acetaldehyde without peak loads. A reduced phagocytotic index of lung macrophages was found in each of the groups exposed to 500 ppm acetaldehyde, the effect being most marked in the group with superimposed peaks of 3000 ppm. Degeneration of the nasal olfactory epithelium was observed in rats uninterruptedly exposed to 500 ppm acetaldehyde. Interruption of the exposure or interruption combined with peak exposure did not visibly influence this adverse effect on the nose. No compound-related effects were seen in rats interruptedly or uninterruptedly exposed to 150 ppm acetaldehyde or interruptedly exposed to 110 ppm with peak loads of 660 ppm. As a consequence 150 ppm acetaldehyde can be considered a 'no-toxic-effect level' in male rats exposed for 6 h/day, 5 days/week, during a 4-week period. It was concluded that the interruption of daily exposure by 1.5 h exposure-free period or by the superimposition of six times 5 min peak exposure periods did not appreciably influence the nasocytotoxic potency of acetaldehyde. Furthermore for inhalation toxicity testing of irritants such as acetaldehyde the use of variable exposure patterns does not seem to produce more relevant toxicity data than the use of uninterrupted daily exposure to a fixed concentration. Chemicals/CAS: acetaldehyde, 75-07-0; Acetaldehyde, 75-07-0

To study the effect of bilateral intranasal electrocoagulation damage on the susceptibility of rats to formaldehyde vapour, male Wistar rats with a damaged or undamaged nasal mucosa were exposed to atmospheres containing 0, 0.1, 1 or 10 ppm formaldehyde vapour during 6 h/day, 5 days/wk for 13 or 52 weeks. Electrocoagulation damage was induced in the anterior third part of the nose. The repair process followed the pattern of wound healing. Loss of turbinates and perforation of the septum were common irreversible findings. After 13 weeks basal cell hyperplasia and squamous metaplasia of the respiratory epithelium, and rhinitis were still visible. After 52 weeks effects attributable to electrocoagulation were slight basal cell hyperplasia and some rhinitis. Major formaldehyde-related adverse effects in the 10 ppm group not subjected to electrocoagulation included growth retardation, reduced urine production, and rhinitis accompanied by squamous metaplasia of the nasal respiratory epithelium. No adverse effects were seen at 0.1 or 1 ppm in rats with an intact nasal mucosa. The principal untoward effects of formaldehyde in electrocoagulation-treated rats seen after 13 and/or 52 weeks comprised increase in basal cell hyperplasia, squamous metaplasia of the nasal respiratory epithelium, damage to the olfactory epithelium at 10 ppm, and focal squamous metaplasia of nasal respiratory epithelium at 0.1 and 1 ppm. Major conclusions were: (a) the rat nose damaged by electrocoagulation is more susceptible to the cytotoxic action of formaldehyde than the undamaged nose, (b) 10 ppm formaldehyde has no adverse effect on organs remote to the site of entry in rats with an undamaged nose, and (c) 1 ppm formaldehyde did not visibly affect the intact nasal epithelium.