The PERICLES research program: an integrated approach to characterize the combined effects of mixtures of pesticide residues to which the French population is exposed.

Due to the broad spectrum of pesticide usages, consumers are exposed to mixtures of residues, which may have combined effects on human health. The PERICLES research program aims to test the potential combined effects of pesticide mixtures, which are likely to occur through dietary exposure. The co-exposure of the French general population to 79 pesticide residues present in the diet was first assessed. A Bayesian nonparametric model was then applied to define the main mixtures to which the French general population is simultaneously and most heavily exposed. Seven mixtures made of two to six pesticides were identified from the exposure assessment. An in vitro approach was used for investigating the toxicological effects of these mixtures and their corresponding individual compounds, using a panel of cellular models, i.e. primary rat and human hepatocytes, liver, intestine, kidney, colon and brain human cell lines. A set of cell functions and corresponding end-points were monitored such as cytotoxicity, real-time cell impedance, genotoxicity, oxidative stress, apoptosis and PXR nuclear receptor transactivation. The mixtures were tested in equimolar concentrations. Among the seven mixtures, two appeared highly cytotoxic, five activated PXR and depending on the assay one or two were genotoxic. In some experiments, the mixture effect was quantitatively different from the effect expected from the addition concept. The PERICLES program shows that, for the most pesticides mixtures to which the French general population is exposed, the toxic effects observed on human cells cannot be easily predicted based on the toxic potential of each compound. Consequently, additional studies should be carried on in order to more accurately define the mixtures of chemicals to which the consumers are exposed, as well as to improve the investigation, prediction and monitoring of their potential human health effects.

Inhibitory Effects of Secondary Metabolites from the Red Alga Delisea pulchra on Swarming Motility of Proteus mirabilis.

Abnormal, uncoordinated swarming motility of the opportunistic human pathogen Proteus mirabilis was seen when a crude extract of the Australian red alga Delisea pulchra was added to the medium. This occurred at concentrations at which growth rate, swimming motility, cell elongation, polynucleation, and hyperflagellation were not affected. One halogenated furanone from D. pulchra inhibited swarming motility at concentrations that did not affect growth rate and swimming motility. Other structurally similar D. pulchra furanones had no effect on swarming, suggesting considerable specificity in the effects of furanones on swarming motility by P. mirabilis.

Eukaryotic interference with homoserine lactone-mediated prokaryotic signalling.

Acylated homoserine lactones (AHLs) play a widespread role in intercellular communication among bacteria. The Australian macroalga Delisea pulchra produces secondary metabolites which have structural similarities to AHL molecules. We report here that these metabolites inhibited AHL-controlled processes in prokaryotes. Our results suggest that the interaction between higher organisms and their surface-associated bacteria may be mediated by interference with bacterial regulatory systems.

The need for standardised broad scale bioassay testing: A case study using the red alga Laurencia rigida.

Two major problems associated with biofouling studies are the lack of broad scale testing and failure to use consistent standards among different assays or studies. To address these issues the activity of two biologically active natural products, elatol and deschloroelatol, isolated from the marine red alga Laurencia rigida, and three commonly used biocides, Nopcocide N-96™, Irgarol 1051™ and Sea-Nine 211™, was compared, in a broad spectrum of bioassays. The activity of the different compounds varied substantially among different bioassay tests. Elatol and deschloroelatol had a narrow range of activity with strongest effects against invertebrate larvae. Both compounds were highly toxic. However, neither compound had strong activity against marine bacteria or the common epiphyte Ulva lactuca. Irgarol 1051 also had a narrow range of activity, only affecting algal settlement strongly. Nopcocide N-96 and Sea-Nine 211 had moderate to strong activity across the spectrum of bioassays, viz. growth of marine bacteria (Vibrio fischeri, Serratia sp.), inhibition of settlement of macroalgae (Ulva lactuca), toxicity (Balanus amphitrite), and inhibition of settlement of invertebrate larvae (Balanus amphitrite, Bugula neritina). Based on the results it is proposed that Sea-Nine 211, because of its broad spectrum activity, be used as a standard for comparative assessments of the antifouling activity of marine natural products and analogues.

Validity and limitations of animal experiments in assessing lung carcinogenicity of cadmium.

Several cadmium compounds have been observed to induce in rats, but in rats only, a dose-dependent increase in lung cancer. A similar sensitivity to lung cancer induction in both humans and rats can be deduced from a comparison of the histogenesis of tumours and the dose response to radiation, since similar numbers of DNA lesions are produced. Since the carcinogenic action of cadmium is limited to the site of deposition, the toxicokinetics of inhaled particles in human and rodents are discussed in relation to the exposure of the respective target cells in both species. It is stressed that the rat may be much more sensitive to the induction of cancer following the retention of poorly soluble compounds. A comparison of the possible dose-effect response in humans and the dose response in rats showed that the shape of the "dose" response cannot be extrapolated. Finally, clonogenicity and DNA repair of tracheal cells sublethally exposed in vitro to cadmium differ significantly in rats and hamsters. This may explain why hamsters exposed in vivo do not develop tumours.

[Evaluation studies of experimental carcinogenesis]. / Evaluation des études de cancérogenèse expérimentale.

In many cases, epidemiological studies demonstrate carcinogenic risk of occupational exposures and industrial processes, but do not allow to assess carcinogenic potential of the various substances involved in exposures (speciation). Expert judgment combining human and animal data is needed for classifying and labelling of the pure substances. For decision aiding purpose, a method was established for reviewing critically experimental carcinogenesis: 1. Standardized toxicological profiles are established according to pure substances, species, strains and administration routes. 2. Methodological evaluation is made using a scheme based on 3 critical parameters: study duration which should extend to the life expectancy of the species under study; sample size, the statistical significance of negative experiments being ascertained depending on size of samples; survival rates of groups, since sufficient numbers of animals should be at risk during most of their life span. 3. Classification of the results for risk assessment, taking into account the relevance of the administration routes.

Increased risk of cataract in patients receiving radiotherapy to the eye: a pilot study.

Of 507 persons in England and Wales identified as having had radiotherapy to the eye or eyes some years previously (after excluding those who had died and were not traced), information suitable for analysis could be obtained on 165. Of these, 23 had developed other eye disease so that the lens could not be examined. Of the other 142, 32 had certainly and one had probably developed cataract. A cataract operation had been performed on 19 persons, compared with an expected operation rate of four out of 142. The increased risk of cataract after radiotherapy to the eye is probably higher than the fivefold excess these figures for operations suggest.

[Activities of pulmonary phospholipases of fetal rats. Variations during development]. / Activités phospholipasiques pulmonaires du foetus de rat. Variations au cours du développement

Turnover of adult rat lung phospholipids implies intervention of phospholipases. This work clearly demonstrates: There is in fetal or adult rat lung an inactive form of phospholipase that is convertible to an active form by the action of lysed platelets. An increase of both active and inactive forms of the fetal enzyme with gestational age. The fact that an important part of these activities, at the time of birth, are in the inactive form implies a control mechanism affecting levels of each form of lung phospholipases. These data are discussed in relation to the possible role of the lung phospholipases in Respiratory Distress Syndrome.