Guy Plomteux

Breast cancer and serum organochlorine residues

Background: Controversy still exists about the breast carcinogenic properties in humans of environmental xenoestrogens (organochlorines), justifying new investigations. Aims: To compare the blood levels of total dichlorodiphenyltrichloroethane (DDT) and hexachlorobenzene (HCB) in samples collected at the time of breast cancer discovery, in order to avoid the potential consequences of body weight change (after chemotherapy or radiotherapy) on the pesticide residue levels. Methods: Blood levels of HCB and total DDT (we calculated total DDT concentrations by adding all DDT and DDE isomers) were compared in 159 women with breast cancer and 250 presumably healthy controls. Risk of breast cancer associated with organochlorine concentration was evaluated. Results: Mean levels of total DDT and HCB were significantly higher for breast cancer patients than for controls. No differences in serum levels of total DDT or HCB were found between oestrogen receptor positive and oestrogen receptor negative patients with breast cancer. Conclusions: These results add to the growing evidence that certain persistent pollutants may occur in higher concentrations in blood samples from breast cancer patients than controls.

Polymorphisms in the CYP 2D6 gene: Association with plasma concentrations of fluoxetine and paroxetine

Most antidepressants are metabolized by cytochrome P450 (CYP) 2D6, and it is well known that there may be significant interindividual variation in the capacity to metabolize xenobiotics. About 7 to 10% of whites are poor metabolisers (PM), and, on the contrary, about 5% are ultrarapid metabolizers (UM), inducing very different rates in the transformation of antidepressants extensively metabolized by CYP 2D6. CYP 2D6 polymorphism can be a potential risk factor for the development of side effects or a reason for the poor efficacy of the treatment. Various probe drugs may be used for phenotyping CYP 2D6, but genotyping is now available using leukocyte DNA and is independent of concomitant drug use. In this study, we used PCR-based methods for the identification of CYP 2D6 genotypes in 49 patients receiving standard doses of fluoxetine or paroxetine and found that plasma concentration of the antidepressant drugs was significantly correlated with genetic status. In one patient who displayed CYP 2D6 gene duplication (UM), paroxetine plasma concentration was extremely low. In PM fluoxetine-treated patients, drug plasma concentration was significantly higher than that seen in extensive metabolizers.

Determination of organochlorine pesticide residues in the blood of healthy individuals.

Abstract Pesticide use is one of several factors that have permitted maintenance of our supply of food in spite of continuing increase of the population. However, the use of biologically active compounds poses potential problems of toxicity. If the compound is used at any stage of food production, residues or derivatives may persist in food and the entire population may be exposed to the trace amounts of the material. The human body burden associated with long-term exposure may or may not be associated with illness. Persistent environmental contaminants such as pesticide residues have long been suspected to be implicated in cancer etiology. Organochlorine chemicals are persistent, lipophilic compounds commonly present in the environment. Some of them demonstrated carcinogenic activity in laboratory animals. Controversy still exists concerning their carcinogenic potential in humans. To answer this question, clinical toxicology laboratories should propose validated methodologies able to identify and quantify pesticide residues in biological samples. An example of chromatographic method dedicated to organochlorine residues is presented here and illustrated by results obtained in a healthy population (104 men, 147 women). Only 17.9% of the samples were free from detectable amounts of pesticides and p,p’-DDE 1,1-dichloro-2,2-bis(p-chlorophenyl) ethylene was the most frequently detected residue (66.5%). Hexachlorobenzene was found at detectable level in 13.5% of the samples.

Venlafaxine: the relationship between dose, plasma concentration and clinical response in depressive patients.

The relationship between plasma drug level of venlafaxine and daily intake was studied in 89 major depressive inpatients. In addition, changes over time in severity were assessed weekly in a subgroup of 22 depressed patients using the Montgomery and Asberg Depression Rating Scale (MADRS) and the Clinical Global Impression improvement scale. The results indicate a moderate correlation between daily doses and plasma concentrations, together with a higher relationship between improvement on the MADRS scale and concentration. Moreover, plasma concentrations (for venlafaxine and its predominant metabolite, O-desmethylvenlafaxine) up to 400 µg/l can be considered as effective, as already suggested in a previous study. No case of venlafaxine discontinuation occurred during the longitudinal study, and the incidence of adverse event, as estimated by the Target Emergent Symptoms and Side-effects scale, was low, suggesting that the drug is well tolerated for such plasma concentrations.

Human exposure to endocrine disrupters: consequences of gastroplasty on plasma concentration of toxic pollutants.

BACKGROUND: Body weight loss occurring after a hypoenergetic diet or a gastroplasty could be followed by an increase in blood concentration of potentially toxic pollutants that can interfere with the hormonal system (endocrine disrupters).DESIGN: Thirty obese individuals recruited for gastroplasty were compared before and after treatment with 45 normal-weight people.MEASUREMENTS: Blood samples were analyzed for DDT, DDE, HCB and PCBs no. 28, 52, 101, 118, 138, 153 and 180, by gas chromatography–mass spectrometry.RESULTS: The results indicate clearly that body weight loss occurring after gastroplasty increases plasma concentration of lipophilic pollutants.CONCLUSION: Gastroplasty increases plasma concentration of organochlorine pesticides and PCBs, which could be a risk factor of endocrine disruption. Future longitudinal research will have to determine if the advantages of body weight loss are reduced by this potentially harmful effect.

Relationship between clinical effects, serum drug concentration, and concurrent drug interactions in depressed patients treated with citalopram, fluoxetine, clomipramine, paroxetine or venlafaxine.

The relationship between clinical effects and plasma concentrations of citalopram, fluoxetine, clomipramine, paroxetine and venlafaxine was studied in 119 cases of major depression. Clinical effects were evaluated using the Clinical Global Impression (CGI) improvement scale. Antidepressants were quantified by a separative chromatographic methodology. Plasma concentrations in responder patients were compared with the plasma concentrations proposed in literature as effective values. We found that the usual therapeutic window is convenient for citalopram and clomipramine, but could be reduced for fluoxetine and increased for venlafaxine and paroxetine. Concurrent drug interactions were also evaluated and clomipramine or citalopram plasma levels were found to be influenced by the presence of associated drugs. A larger study is needed, taking into account not only plasma concentrations and clinical effects, but also some pharmacokinetic data, especially the metabolic activity characterising the patient, and the presence or not of associated drugs. Copyright

Methadone maintenance treatment: is it possible to adapt the daily doses to the metabolic activity of the patient?

Controversy still exists concerning the proper daily dose of methadone to be used in opiate dependency treatment. Because it is admitted that serum methadone concentration may be significantly correlated with the amount of drug available at the receptor level, it could be interesting to predict the methadone daily doses necessary to reach such a serum concentration. The authors have attempted to correlate the serum methadone level with the daily intake, considering the metabolic activity of the patients. A poor correlation was found between methadone doses and methadone serum concentrations (r2 = 0.0409, p = 0.048). The test used to determine the metabolic activity of patients is the 6-OH cortisol/17-OH corticosteroids ratio in urine. This urinary 6-OH cortisol/17-OH corticosteroids ratio was tested because cortisol is metabolized through the same P450 cytochromes as methadone, namely cytochrome P450 3A4. This determination could be of interest because it could be tested before methadone administration to predict optimal doses. But when the authors tried to correlate the methadone serum concentration with the steroid ratio, they failed to find a significant correlation (r2 = 0.0046, N.S.), even when they took into account the daily doses (r2 = 0.0015, N.S.), most probably because of some limitations of the cortisol ratio.

Evaluation of EMIT tox benzodiazepine and barbiturate assays on the Vitalab Viva analyser and FPIA on the Abbott ADx analyser

Abstract We evaluated the performance of the Emit® tox benzodiazepine and barbiturate assays (Dade Behring) and fluorescence polarisation immunoassay (FPIA) (Abbott) for use with serum determinations in preliminary therapeutic drug monitoring or acute drug intoxication detection. Performance, as indicated by CVs, of the Emit® tox benzodiazepine and barbiturate assays and FPIA showed that both immunochemical techniques are precise and have good reproducibility. For within-run studies, results from benzodiazepine determinations showed maximum CV values of 1.91% for the Emit® method and 2.65% for FPIA; results from barbiturate determinations showed maximum CV values of 2.01% for the Emit® method and 1.89% for FPIA. For between-run studies, results from benzodiazepine determinations showed maximum CV values of 1.79% for the Emit® method and 1.12% for FPIA; results from barbiturate determinations showed maximum CV values of 2.09% for the Emit® method and 2.02% for FPIA.

The Effect of Intravenous Administration of Web 2086 on PAF-Induced Platelet Aggregation in Healthy Friesian Calves

The in vivo ability of the specific PAF-antagonist WEB 2086, a thienotriazolodiazepine, to inhibit platelet-activating factor (PAF) in cattle was investigated by in vitro determination of platelet aggregation curves. WEB 2086 was infused intravenously into a group of 5 healthy male Friesian calves in a dose of 3 mg/kg over 1 min. The resultant inhibition peaked between 30 min and 1 h after administration of WEB 2086. The inhibition was significantly reduced after 3 h and became non-significant after 6 h, but maximal pre-treatment aggregation had not been restored by 24 h after the injection of WEB 2086. These results confirm previous results obtained in vitro and suggest that WEB 2086 is a potent antagonist of PAF activity in calves. They also suggest that further clinical studies with WEB 2086 in cattle are desirable.

Effets perturbateurs endocriniens des pesticides organochlores.

Abstract Xenoestrogens such organochlorine pesticides are known to induce changes in reproductive development, function or behaviour in wildlife. Because these compounds are able to modify the estrogens metabolism, or to compete with estradiol for binding to the estrogen receptor, it may be possible that these products affect the risk of developing impaired fertility, precocious puberty or some kinds of cancer in man. Le plus ancien récit de lutte contre la pollution remonte à une légende indienne racontant que la divinité Sing-bonga était incommodée par les émanations des fours dans lesquels les Asuras fondaient leurs métaux (1). Evidemment depuis, la problématique n–a cessé de s–accroître et la contamination de la Terre par de nombreux polluants est devenue aujourd–hui un problème majeur de notre Société. La protection de notre environnement est une question capitale qui doit être respectée malgré la pression économique actuelle et qui ne cessera de croître au cours des prochaines années même si l–identification objective et indiscutable de ce qui est essentiel – donc devant être prioritairement garanti sur la planète – est difficile à cerner (2). « Un oiseau en mauvais état ne pond pas de bons oeufs » disait un proverbe grec. Mais ce n–est qu–à partir de la seconde moitié du XXème siècle que les toxicologues ont commencé à identifier les effets qu–avaient entraînés à l–échelle mondiale les pollutions émises aux XIXème siècle sur la faune sauvage et sur le cheptel (3). L–histoire contemporaine des pesticides industriels commence vers 1874 (synthèse des organochlorés) et se poursuit tout au long de ces 2 siècles en passant par la synthèse des organophosphorés (1950), des carbamates (1970) et des pyréthroïdes (1975) (4). Le dichlorodiphényltrichloroéthane (DDT) a été synthétisé pour la première fois par un étudiant en cours de préparation de sa thèse de doctorat : Othmer Zeidler. La production, reprise par les entreprises F.Mayo puis par la Geigy Co. a d–abord intéressé l–armée, puis l–agriculture. Dès la fin de la 2ème guerre mondiale, des mises en garde furent lancées à propos des effets nocifs du produit (4). Un déclin des populations de grives, d–aigles chauves, d–orfaies et de mammifères consommateurs de poissons fut constaté à partir des années 50 et dénoncé par Rachel Carson dans son célèbre appel du « Silent Spring » de 1962. Bien qu–il soit interdit en Occident depuis les années 70, ce produit a été tellement utilisé et présente une rémanence si longue qu–une contamination ubiquitaire existe aujourd–hui encore. De plus, ce produit continue à être produit aux USA pour être utilisé à des fins de démoustification dans les pays en voie de développement. Il en va de même de l–Hexachlorobenzène (HCB), un autre organochloré dont l–usage est interdit sous nos latitudes, mais reste fréquent dans d–autres pays. Ces deux exemples indiquent que le problème de la contamination continue à nous concerner, même pour des produits dont l–usage est aujourd–hui strictement réglementé ou interdit. Des effets sur la faune semblent encore actuellement devoir être attribués à ces produits. La diminution de la population des phoques dans la mer de Wadden pourrait être due à la forte contamination en composants organochlorés des poissons dont ces phoques se nourrissent (5). Exposé au DDT et à son métabolite dichlorodiphenyldichloroéthylène (DDE), le Seratherodon mossambicus présente une réduction de la sécrétion de cortisol par une action toxique cytospécifique sur l–axe hypothalamo-hypophysaire (6). Des travaux récents ont montré que le DDT et le DDE se lient chez les oiseaux et les mammifères au moyen de liaisons covalentes aux cellules de la zona fasciculata - homologue du tissu interrénal du poisson - induisant des microhémorragies. Cette « défaillance » cortisolique peut s–accompagner d–une perturbation du métabolisme glucidique et notamment d–un taux élevé de glycogène hépatique (7). Les pesticides organochlorés (DDT, DDE) entraînent également des perturbations d–ordre métabolique chez certaines espèces d–oiseaux, notamment le faucon pèlerin en Grande Bretagne et les oiseaux piscivores des grands lacs nord américains où l–on a constaté au cours des années 1960 que leur reproduction était menacée et qu–une des manifestations les plus évidentes des perturbations observées était le taux élevé de malformations (8). Des mortalités élevées de poissons ou de coquillages ont été rapportées dans des élevages situés à proximité des zones d–épandage de pesticides organophosphorés et de carbamates. En 1991, la dispersion aérienne de fenitrothion dans le but de provoquer la démoustication en Languedoc a été à l–origine de la perte de plusieurs tonnes de crevettes japonaises. L–utilisation de trichlorfon et de dichlorvos comme antiparasitaires dans des fermes d–élevages de saumons a provoqué des épisodes de mortalité importante (9).