[Reconsideration of the role of aflatoxins in public health]. / Le rôle des aflatoxines en santé publique à reconsidérer.

The pathogenicity of aflatoxins for human has been largely demonstrated. Although aflatoxin contamination of some foodstuffs has been unquestionably established, stress should be laid upon a certain lack of information: some of the affected foodstuffs have been "forgotten" in the enumeration of contaminated products (especially soybeans); relations between mycotoxins and food balance have not yet been taken into account: for instance, the influence of some vitamins, of various compounds (carotenoids, methionine, ...), influence of deficiency in proteins (often very important in Africa) etc... aflatoxin bioavailability has not sufficiently been examined (particularly that of milk aflatoxin M1.); concerning aflatoxin evaluation in contaminated products, it should be known that their distribution is very irregular. Sampling and following analysis should thus be carried out most carefully; for these motives, some conditions and likewise regulations would can again scrutinized.

[Specific induction by phorbol ester of the gene transcription and of the activity of ornithine decarboxylase in two control and transformed epithelial cell lines. Modulator effect of anti-inflammatory agents]. / Induction spécifique par l'ester de phorbol de la transcription du gène et de l'activité d'ornithine décarboxylase dans deux lignées de cellules épithéliales témoins et transformées. Effet modulateur des agents anti-inflammatoires.

The mechanism of ornithine decarboxylase (ODC) induction by phorbol ester (TPA) has been studied in two permanent epithelial cell lines, a control (Ctr) and a Benzo (a) pyrene transformed line (BaP-tr); the degree of ODC gene expression (ODC-mRNA) was evaluated in comparison to the ODC activity. A small dose of TPA (4 x 10(-8) M) highly induced ODC activity in these cells. The induction levels differed however, corresponding respectively to 4:1 (induced: basal ODC) in Ctr cells and to 2:1 in BaP-tr cells. This difference reflected the variation of ODC gene expression; the ODC-mRNA induction was 6:1 in Ctr cells and 3:1 in BaP-tr cells. Repetitive TPA treatment decreased the ODC induction in these cells, as compared to that resulting from a single TPA treatment. Studies of ODC modulation were performed in presence of anti-inflammatory agents. In the two cell lines, Indomethacin (anti-cyclooxygenase) did not change the level of ODC induction by TPA. Nordihydroguaiaretic acid (NDGA, anti-lipoxygenase) inhibited this induced ODC. These results differed from that obtained in vivo in mouse skin. Dexamethasone (DXME, anti-phospholipase A2) showed different action according to treatment time. Used together with TPA (t0), DXME inhibited ODC induction by the carcinogen; with three hours delay after TPA (t3), DXME treatment stimulated ODC in the cells. This divergent action may be reproduced by Actinomycin D, while Cycloheximide only exhibited constant inhibition. Studies now in progress suggested that the inhibition of TPA induced ODC by DXME may reflect ODC gene repression, as for the stimulating effect it could be related to ODC post-transcriptional modulation, owing to the decrease of proteolytic action.

The concept of the acceptable daily intake: an historical review.

In the first section the sequence of events is outlined which leads to the author's proposal to consider the concept of acceptable daily intake (ADI) for pesticide residues. He developed his theory referring to specific aspects during meetings with experts on the toxicological evaluation of chemical agents which become introduced into foodstuffs intentionally or unintentionally. These meetings were organized periodically by the European Council or Joint FAO/WHO Expert Committees on food additives (JECFA) or pesticide residues (JMPR). The general principles of the ADI evaluation are briefly described as being based on the determination (after extended absorption) of a no-effect dose level in an appropriate animal species; followed by the application, for the extrapolation of the results in animals to humans, of safety factors taking into account the interspecies sensitivity variations and individual sensitivity variations in the groups of essentially heterogeneous human consumers. It is pointed out that the ADI value, which depends on a series of factors, is not a constant, but a guide serving to calculate the admissible limits of diverse chemical agents incorporated in foodstuffs. It must take into account the usual normalities between medium terms of consumption varying a lot with the countries and the various consumer groups. It is clearly noted that, because of the fluctuations in the type and the quantities of absorbed diets, the ADI is in reality an integrated value with regard to the time, a notion that is often forgotten. Other ideas are developed, in particular on the adoption of a temporary ADI and on the concept of a non-specified ADI.

[Recent progress in the evaluation of the dangers of chemical carcinogens]. / Progrès récents dans l'évaluation des dangers des agents chimiques cancérogènes.

The paper begins with a brief historical account of the production of cancers through exposure to chemicals, first in humans, then in animals, followed by the identification of chemically defined agents. Such agents have progressively been discovered in the most diverse chemical families. The present classification of chemical carcinogens includes those demonstrated as carcinogenic for humans by adequate epidemiological studies and those considered, on more or less limited basis, as probably or possibly carcinogenic for humans. The first category is divided into three groups: complex mixtures-defined chemicals-industrial operations. The materials and compounds of the last two categories are called "potential carcinogens". The present international trend is to consider them as dangerous for humans as long as their innocuousness has not been demonstrated. The author stresses that the compounds of the three categories are either manufactured or developed by man, or of natural origin. The latter seem, by far, to cause the highest percentage of cancers in humans. Then he develops, in their general outline, the pluridisciplinary methodological approaches in view to revealing the carcinogenic potentialities of compounds to which man can be exposed in various fields (occupational, food, therapeutic, household,...). This leads him to underline the factors of uncertainty involved by the extrapolation to humans of the results of animal experimentation and the importance of observations on groups of humans. He also stresses the multifactors which intervene in the various steps of evolution towards malignancy (initiation, promotion, influence of synergistic or antagonistic factors-role of "free radicals" the type of which is the superoxyde anion radical O2-.). He emphasizes the difficulties of interpretation resulting from the multifactorial nature of the processes of malignancy, as well as the interest of revealing the intimate mechanisms of activity (genotoxic mechanisms with the transformation of certain genes: protooncogenes to oncogenes, epigenetic mechanisms); this demonstration becomes more and more performant thanks to the spectacular progress of basis sciences to which cancer evaluation methodology appeals more and more. Evaluation of carcinogenic risks which, together with early diagnosis, constitutes a fundamental basis of cancer prevention is thus considerably improved. The author is thus led to discuss the possibility of setting threshold values, at least for some types of carcinogenic chemicals. In the end, he insists upon the necessity of an active international cooperation for carcinogenicity studies, either experimental or epidemiological.

[Toxicologic and ecotoxicologic problems posed by air pollution in urban environments]. / Problèmes toxicologiques et écotoxicologiques posés par la pollution de l'air dans l'environnement urbain.

After defining the terms "toxic" and "ecotoxic", general notions are given on: 1) the main sources of urban pollution; 2) the main factors having an influence on qualitative and quantitative composition of urban pollution; 3) the main risks for man, urban ecosystems and physical environment (acute and long term noxious effects); the importance of interactions is stressed; 4) the general principles of prevention. A special chapter is devoted to "indoor pollution". Microbiological pollution is excluded.

Chronic toxicity/carcinogenicity study of trans-anethole in rats.

A chronic feeding study was carried out in rats with trans-anethole. The test substance was administered in the diet to groups (n = 26-78) of 312 male and 312 female Sprague-Dawley rats at concentrations of 0, 0.25, 0.5 and 1% for 117-121 wk. The average intakes of trans-anethole varied from 105-550 mg/kg body weight/day. No apparent treatment-related reactions were noted. The only effect was a transient retardation of body-weight gain. No excess mortality was caused by the treatment. No abnormalities related to treatment were seen on necropsy except for reduced adiposity in the highest dose groups. Haematological assessments did not reveal any changes related to treatment. Histological examination revealed certain non-neoplastic and neoplastic lesions common in older rats. The incidence of some hepatic lesions was significantly higher in some treated groups than in controls: altered cell foci (females of the 1% group), nodular hyperplasia (males of the 0.5% group and males and females of the 1% groups), benign tumours (females of the 1% group) and malignant tumours (females of the 1% group). The results are compared with those of previous investigations. The authors of this study stress that the low incidence of hepatocarcinomas is restricted to a single species and sex and to the highest dose tested. This pattern of species, sex and dose dependency strongly suggests that metabolic and pharmacokinetic studies will be helpful in interpreting the significance of the rat tumours with regard to the safe consumption of trans-anethole by man. The changes observed in this chronic feeding study are not thought to be of genetic origin and consequently trans-anethole does not constitute a significant carcinogenic risk to man. Further studies are in progress to substantiate this conclusion.

Effect of long-term ingestion of asbestos fibres in rats.

The effects of ingested asbestos fibres were studied in Wistar Han rats. Chrysotile and a mixture of chrysotile/crocidolite (75%/25%) in palm oil were given for 24 months to 70 males and 70 females per group (daily doses 10, 60 and 360 mg); one control group was fed with normal diet, a second with normal diet plus palm oil. The animals were observed for a further 6 months after the end of the treatment. The results indicate that ingestion of asbestos fibres at high doses had no toxic effects and did not affect animal survival; in addition, there was no evidence of carcinogenic effects.

[Epigenetic mechanism of tumor promotion. Interrelationship between inflammation and ornithine decarboxylase activity induced in vitro by the carcinogenic 12-O-tetradecanoyl-phorbol-13-acetate]. / Mécanisme épigénétique de la promotion tumorale. Interrelation entre l'inflammation et l'activité d'ornithine décarboxylase induites in vitro par le cancérogène 12-O-tetradecanoyl-phorbol-13-acetate.

Topical application of 2 micrograms 12-O-tetradecanoyl-phorbol-13-acetate (TPA) regularly induced two early events in mouse skin: inflammatory reaction localized in dermal compartment and stimulation of ornithine decarboxylase activity in epidermal cells, in relation to polyamine synthesis and cell division. These reactions were followed, after 48 hrs. by an epidermal hyperplasia. At this stage, another TPA treatment induced a strong ODC activity concurrent with severe inflammation of the dermis. Inhibition of the synthesis of inflammatory factors may antagonize TPA-induced ODC, but the protective potencies differs according to the evolutive stages of the cell. After the first TPA treatment the anti-inflammatory compounds dexamethasone and indomethacin effectively inhibited ODC activity. In contrast during the proliferative stage epidermal cell function may be less dependent on inflammatory factors; thus only partial protection was observed with the inflammatory inhibitors.