[Levels of dichlorodiphenyltrichloroethane internal exposure levels in pregnant women of Xiamen and influencing factors].

Objective: To investigate the level of and factors influencing internal exposure to dichlorodiphenyltrichloroethane (DDT) in pregnant women. Methods: In all, 1 064 pregnant women were recruited in a hospital of Xiamen. Participants were asked to complete a questionnaire to obtain data on sociodemographic characteristics and lifestyle. Peripheral venous blood and cord blood samples were collected. Of the 1 064 pregnant women, 600 were enrolled in this study after completing the questionnaire and providing peripheral venous blood and cord blood. Among those women, 150 were selected randomly using a systematic sampling method. A gas chromatography coupled electron capture detector was used to determine the concentration of six DDT homologues: p,p'-dichlorodiphenyltrichloroethane (p,p'-DDT), o,p'-dichlorodiphenyltrichloroethane (o,p'-DDT), p,p'-dichlorodiphenyldichloroethane (p,p'-DDD), o,p'-dichlorodiphenyldichloroethane (o,p'-DDD), p,p'-dichlorodiphenylethylene (p,p'-DDE), and o,p'-dichlorodiphenylethylene (o,p'-DDE) . Pregnant women were divided into two groups according to DDT concentration: a low concentration group (detection value≤P50) and a high concentration group (detection value>P50). multivariate logistic regression was used to analyze the association between the DDT levels and potential influencing factors which investigated in the questionnaire. Results: The detection rates of p,p'-DDT, o,p'-DDT, p,p'-DDD, o,p'-DDD, p,p'-DDE and o,p'-DDE in the peripheral venous blood samples from the 150 pregnant women were 83.3% (125), 29.3% (44), 58.0% (87), 24.0% (36), 82.0% (123), and 34.7% (52), respectively. The median concentrations were 1.56, 0.03, 0.07, 0.03, 0.93 and 0.03 µg/ml, respectively. The detection rates of p,p'-DDT, o,p'-DDT, p,p'-DDD, o,p'-DDD, p,p'-DDE and o,p'-DDE in the cord blood samples were 69.3% (104), 10.7% (16), 29.3% (44), 20.7% (31), 81.3% (122) and 45.3% (68), and the median concentrations were 0.41, 0.03, 0.03, 0.03, 0.42 and 0.03 µg/ml, respectively. The concentration ranges in the low and high DDT concentration groups which contained 75 respondents respectively were 0-3.69 and 3.74-82.09 µg/ml, respectively. In the single-factor analysis, the number (percentage) of those who consumed seafood " rarely" , "less than twice a week" , and " twice a week or more" was 15 (20.3%), 22 (29.7%), and 37 (50.0%), respectively, in the low concentration group, and 4(5.3%), 20(26.7% ), and 51(68.0% ) in the high concentration group (χ2=8.69, P=0.013). The results of the multivariate logistic regression analysis indicate that pregnant women who consume seafood less than twice a week, twice a week or more have higher peripheral blood DDT concentrations compared with those who rarely consume seafood. The OR (95% CI) values were 1.14 (1.08-1.21), 2.11 (1.55-2.85), respectively. Conclusion: The exposure level of pregnant women to DDTs in the Xiamen area is higher than that of women in other regions. High seafood intake is a risk factor for internal exposure to DDTs.

Prenatal exposure to persistent organic pollutants in association with offspring neuropsychological development at 4years of age: The Rhea mother-child cohort, Crete, Greece.

BACKGROUND: Persistent Organic Pollutants (POPs) are highly-resistant compounds to environmental degradation and due to fat solubility they bioaccumulate through the food chain. As they cross the placenta, in utero exposure to POPs could disrupt child neurodevelopment as they are considered to be neurotoxic. AIMS: We examined whether in utero exposure to levels of different POPs is associated with offspring cognitive and behavioral outcomes at 4years of age in a mother-child cohort in Crete, Greece (Rhea study). METHODS: We included 689 mother-child pairs. Concentrations of several polychlorinated biphenyls (PCBs) and other organochlorine compounds (dichlorodiphenyl dichloroethene [DDE], hexachlorobenzene [HCB]) were determined in maternal serum collected in the first trimester of pregnancy by triple quadrupole mass spectrometry. Neurodevelopment at 4years was assessed by means of the McCarthy Scales of Children's Abilities. Behavioral difficulties were assessed by Strengths and Difficulties Questionnaire and Attention Deficit Hyperactivity Disorder Test. Linear regression analyses were used to estimate the associations between the exposures and outcomes of interest after adjustment for potential confounders. RESULTS: Children with "high" HCB concentrations (≥90th percentile) in maternal serum, demonstrated decreased scores in perceptual performance (adjusted ß=-6.07; 95% CI: -10.17, -1.97), general cognitive (adjusted ß=-4.97; 95% CI: -8.99, -0.96), executive function (adjusted ß=-6.24; 95% CI: -10.36, -2.11) and working memory (adjusted ß=-4.71; 95% CI: -9.05, -0.36) scales at 4years of age. High exposure to PCBs (≥90th percentile) during pregnancy was associated with a 4.62 points reduction in working memory score at 4years of age (95% CI: -9.10, -0.14). Prenatal exposure to DDE, HCB and PCBs was not associated with child behavioral difficulties. CONCLUSIONS: The findings suggest that prenatal exposure to HCB and PCBs may contribute to reduced cognitive development at preschool age. Our results raise the possibility that exposure to HCB may play a more important role in child cognition than previously considered.

Effects of adrenolytic mitotane on drug elimination pathways assessed in vitro.

Mitotane (1,1-dichloro-2-(o-chlorophenyl)-2-(p-chlorophenyl)ethane, o,p'-DDD) represents one of the most active drugs for the treatment of adrenocortical carcinoma. Its metabolites 1,1-(o,p'-dichlorodiphenyl) acetic acid (=o,p'-DDA) and 1,1-(o,p'-dichlorodiphenyl)-2,2 dichloroethene (=o,p'-DDE) partly contribute to its pharmacological effects. Because mitotane has a narrow therapeutic index and causes pharmacokinetic drug-drug interactions, knowledge about these compounds' effects on drug metabolizing and transporting proteins is crucial. Using quantitative real-time polymerase chain reaction, our study confirmed the strong inducing effects of o,p'-DDD on mRNA expression of cytochrome P450 3A4 (CYP3A4, 30-fold) and demonstrated that other enzymes and transporters are also induced (e.g., CYP1A2, 8.4-fold; ABCG2 (encoding breast resistance cancer protein, BCRP), 4.2-fold; ABCB1 (encoding P-glycoprotein, P-gp) 3.4-fold). P-gp induction was confirmed at the protein level. o,p'-DDE revealed a similar induction profile, however, with less potency and o,p'-DDA had only minor effects. Reporter gene assays clearly confirmed o,p'-DDD to be a PXR activator and for the first time demonstrated that o,p'-DDE and o,p'-DDA also activate PXR albeit with lower potency. Using isolated, recombinant CYP enzymes, o,p'-DDD and o,p'-DDE were shown to strongly inhibit CYP2C19 (IC50 = 0.05 and 0.09 µM). o,p'-DDA exhibited only minor inhibitory effects. In addition, o,p'-DDD, o,p'-DDE, and o,p'-DDA are demonstrated to be neither substrates nor inhibitors of BCRP or P-gp function. In summary, o,p'-DDD and o,p'-DDE might be potential perpetrators in pharmacokinetic drug-drug interactions through induction of drug-metabolizing enzymes or drug transporters and by potent inhibition of CYP2C19. In tumors over-expressing BCRP or P-gp, o,p'-DDD and its metabolites should retain their efficacy due to a lack of substrate characteristics.

Levels of DDT and its metabolites in placenta, maternal and cord blood and their potential influence on neonatal anthropometric measures.

Previous studies of in utero exposure to dichlorodiphenyltrichloroethane (DDT) have shown mixed results for the harmful effects on fetal growth and development. This cross-sectional study was designed to: (1) examine the extent of DDT exposure in 1578 women, aged 28.5±6.0 who delivered between June 2005 and 2006 in the area of Al-Kharj, Saudi Arabia; and (2) assess its influence on neonatal anthropometric measurement of newly born babies. DDT and its metabolites, namely 1,1-dichloro-2,2-bis (p-chlorophenyl) ethylene (p,p'-DDE), 1,1-dichloro-2,2-bis (p-chlorophenyl) ethane (p,p'-DDD) and 1,1,1-trichloro-2,2' bis (p-chlorophenyl) ethane (p,p'-DDT) were measured in cord and maternal serum as well as placenta by Gas Chromatography coupled with an Electron Capture Detector (GC/ECD). p,p'-DDE was detected in 28.3% of cord and 54.4% of maternal serum, reflecting past exposure, whereas the p,p'-DDT was only found in 0.46% cord and 1.2% maternal samples. As expected the p,p'-DDE cord levels (0.197±0.961µg/L) were 2.8 times lower than the maternal levels (0.551±1.778µg/L), and both were significantly correlated (r=0.517) suggesting its transplacental transfer. The picture was different in placental tissues. p,p'-DDE and p,p'-DDT were detected in 84% and 99% of placental tissues, with the highest p,p'-DDT in placental tissues (29.62±158.282µg/kg dry wt.) compare to p,p'-DDE (10.167±18.851µg/kg dry wt.). In general, the presence of DDT metabolites in our participants indicates that these chemicals are still relevant despite the fact that they have been banned or restricted in the study area for many years. Our results support the view for an association between low in utero exposure to DDT and the anthropometric development of the fetus leading to a reduction in its head circumference, crown-heel length, birth weight and birth height. Since the reduction in these measures was independent of gestational age and/or preterm births, our findings suggest a detrimental effect of the DDT exposure on fetal growth. Neonatal anthropometric measures are considered as an important tool to detect newborns at higher risk of morbidity and impairment of growth. Efforts should be made to decrease exposure of women of reproductive age and to examine maternal DDT exposure in relation to long-term impact on health.

Levels of persistent organic pollutant and their predictors among young adults.

Exposure to persistent organic pollutants (POPs), such as polychlorinated biphenyls (PCBs), dichlorodiphenyldichloroethane (p,p'-DDE), and hexachlorobenzene (HCB) continues to be of concern due to their ubiquitous distribution and high persistence. Current toxicant body burden is still a primary concern within the Akwesasne Mohawk Nation since other studies conducted within the community have shown relationships between these POPs and endocrine disruption. In this article we describe the levels of these toxicants in young adults of the Akwesasne Mohawk Nation between the ages of 17 and 21 years of age (mean age 18.1 years), and investigate potential influences of their current body burden. Seventeen congeners in fourteen chromatographic peaks were detected in 50% or more of the individuals sampled (geometric mean [GM] of the sum of these congeners=0.43 ppb). Congeners 118, 138[+163+164] and 153 had the highest rate of detection (≥98%) within the Akwesasne young adults. Of the other organochlorines, HCB (GM=0.04 ppb) and p,p'-DDE (GM=0.38 ppb) were found in 100% and 99% of the sample respectively. Significantly higher levels of PCBs were found among individuals who were breastfed as infants, were first born, or had consumed local fish within the past year. When compared to levels of p,p'-DDE, HCB, and 13 specific congeners reported by the CDC for youth between the ages of 12 and 19 years, the geometric means of several congeners (CBs 99, 105, 110, and 118) among the Akwesasne were higher than the reported CDC 90th percentile. In contrast, levels of CB 28 in Akwesasne young adults were ~50% or less than those of the CDC cohort. p,p'-DDE and HCB levels were generally higher in the CDC cohort (GM of 0.516 and 0.065 ppb, respectively for Mohawks vs. 2.51 and 0.123, respectively, for CDC). Concentrations of non-persistent PCBs among this sample of Akwesasne young adults were higher than those reported by the CDC suggesting continued exposure, but lower than those associated with severe contamination. Additional research into the concentration trends of individual PCB congeners within Akwesasne youth and young adults is warranted to further improve our insight into the determinants and influences of organochlorine concentrations within members of the Akwesasne community.

Human exposure to persistent organic pollutants in West Africa--a temporal trend study from Guinea-Bissau.

BACKGROUND: Humans, independent on where they live, are exposed to complex and various mixtures of chemicals, including persistent organic pollutants (POPs). The variability of the exposure depends on sources of the chemicals and is influenced by e.g. geography, social and cultural heritage. While exposures to POPs are frequently studied in populations from developed industrial countries, very little is known on levels and trends of POPs in developing countries, especially in Africa. OBJECTIVES: The aim of the present study was to investigate levels and temporal trends of POPs in adults from Guinea-Bissau. METHODS: Serum samples were obtained from an open cohort of police officers in Guinea-Bissau. Repeated samples from 33 individuals were obtained at five time points between 1990 and 2007, in all 147 samples. Pooled serum samples were extracted and cleaned-up prior to analysis by gas chromatography and mass spectrometry. The concentration of 1,1,1-trichloro-2,2-bis(4-chlorophenyl)ethane (4,4'-DDT) and its metabolites, polychlorinated biphenyls (PCBs), polybrominated diphenyl ethers (PBDEs) and hexachlorocyclohexanes (HCHs) were determined. RESULTS: The major POP found in all samples was 1,1-dichloro-2,2-bis(4-chlorophenyl)ethene (4,4'-DDE) followed by 4,4'-DDT. 4,4'-DDE, 4,4'-DDT, PCBs and beta- and gamma-HCH were significantly decreasing over time. The PBDEs were found at low concentrations, with an increasing temporal trend for BDE-153. CONCLUSION: National and international management may be behind the observed decreased organohalogen compound concentrations in humans from Guinea-Bissau from the early 1990's and onwards, similarly to the development of these compounds in humans from industrial countries. In contrast, PBDEs follow a trend of increasing concentrations even though at low levels.

Outcome of in-vitro fertilization treatment and DDT levels in serum and follicular fluid.

BACKGROUND: Although p,p'-dichlorodiphenyltrichloroethane (DDT) is banned for agricultural purpose in Saudi Arabia, it is occasionally used to control vector-borne diseases in certain regions of the country. MATERIAL/METHODS: A case-control study was designed to investigate the possible effects of DDT and its metabolites on pregnancy and fertilization rate outcome. The study population was composed of 619 Saudi women (age 19-50 years) who sought in-vitro fertilization (IVF) treatment between 2002 and 2003. RESULTS: p,p'-DDE, the main metabolite of DDT, was the most frequently detected residue in serum or follicular fluid, with mean values of 1.646 microg/L and 0.407 microg/L, respectively. After controlling for many potential confounding variables, multiple logistic regression analysis revealed no association between pregnancy outcome or fertilization rate and p,p'-DDE levels in serum or follicular fluid. CONCLUSIONS: The inability to identify an effect may be related to the comparatively low concentrations of DDE in our population. But because p,p'-DDE was detected in the serum of 77.7% our participants, it should be considered as a matter of public heath concern. Currently there is no active source of DDT in our region; therefore, further studies are needed to identify sources in order to develop preventive measures because we can not exclude its potential reproductive toxicity.

Concentrations of chlorinated and brominated contaminants and their metabolites in serum of harbour seals and harbour porpoises.

Harbour seals (Phoca vitulina) and harbour porpoises (Phocoena phocoena) are top predators in the North Sea and consequently accumulate a variety of pollutants in their tissues. Concentrations of polychlorinated biphenyls (PCBs), polybrominated diphenyl ethers (PBDEs) and their hydroxylated metabolites (HO-PCBs and HO-PBDEs) were measured in serum of wild harbour seals (n=47) and captive harbour porpoises (n=21). Both species exhibit long life spans and do not have extreme situations, such as complete fasting during periods of lactation, in their annual cycles. For PCBs, concentrations in adult males were slightly higher than in juveniles and lowest in juvenile females. For PBDEs, juveniles have higher levels than adult males and females, probably as a consequence of lactational transfer. However, differences between these age-gender groups were not statistical significant, indicating that individual variation was limited within each species, even without knowing the feeding status of the animals. Body condition, particularly emaciation, has a major influence on the levels of chlorinated and brominated contaminants in serum. Profiles of PCBs were CB 153>CB 138>CB 187>CB 180 and CB 153>CB 138>CB 149>CB 187>CB 180 for harbour seals and porpoises respectively. For PBDEs, BDE 47 was the predominant congener followed by BDE 100 and 99 in both species. In harbour seals, concentrations of sum PCBs (median: 39,200 pg/ml) were more than 200 times higher than levels of sum PBDEs (median: 130 pg/ml) and almost 10 times higher than concentrations of sum HO-PCBs (4350 pg/ml). In harbour porpoises, concentrations of sum PCBs (median: 24,300 pg/ml) were about 20 times higher than concentrations of PBDEs (median: 1300 pg/ml). HO-PCBs were detected in only 4 harbour porpoises and this at very low concentrations. Naturally-produced MeO-PBDEs were only found in harbour porpoises at concentrations ranging from 120 to 810 pg/ml. HO-PBDEs were not found in any species. In general, harbour seals accumulate less compounds and have mostly lower concentrations than harbour porpoises possibly as a result of a better developed metabolism.

Dichlorodiphenyldichloroethane and polychlorinated biphenyls: intraindividual changes, correlations, and predictors in healthy women from the southeastern United States.

Dichlorodiphenyldichloroethane (DDE) and polychlorinated biphenyls (PCB) are widespread environmental contaminants that have been postulated to increase the risk of diseases such as non-Hodgkin's lymphoma, breast cancer, as well as lead to early menopause. Studies assessing the effect of organochlorine exposure often can only measure organochlorine levels once, such as at study enrollment, which may not be an etiologically relevant time period. We assessed the temporal changes in DDE and PCBs and the predictors of those changes using interview data and DDE and PCB measures collected from 123 women who were enrolled in a baseline study from 1978 to 1982 and followed up in 2003 to 2004. Baseline and follow-up organochlorine levels were compared using Spearman correlations (r(s)), and predictors of the rate of change in log concentration were evaluated using linear regression models. Although serum concentrations dramatically declined (median follow-up to baseline concentration ratio was 16% for DDE and 45% for PCB), baseline and follow-up measures were strongly correlated for DDE (r(s)=0.72) and moderately correlated for PCBs (r(s)=0.43). Prediction of follow-up PCB levels was substantially improved (r(s)=0.75) with data on initial concentration, length of lactation, baseline body mass index, and percent change in body fat, whereas DDE prediction improved slightly (r(s)=0.83) with data on lactation and baseline body mass index. These findings suggest that a single organochlorine measure provides considerable information on relative ranking at distant times and that the predictive power can be improved, particularly for PCBs, with information on a few predictors.

Placental transfer of DDT in mother-infant pairs from Northern Thailand.

The present study objective was to investigate ratios and correlation coefficients between dichlorodiphenyltrichloroethane (DDT) compounds in cord and maternal sera of mother-infant pairs from northern Thailand. The study site was located in Chiang Dao District of Chiang Mai Province which was an agricultural and former malaria endemic area. DDT compounds were analyzed in 88 cord and maternal serum samples using gas chromatography-electron capture detection (GC-ECD). p,p'-DDE (1,1-dichloro-2,2-bis(p-chlorophenyl)ethylene) was the major component and detected in every cord and maternal serum samples with geometric means of 1,255 and 1,793 n g(-1) lipids, respectively. p,p'-DDT (1,1,1-trichloro-2,2-bis(p-chlorophenyl)ethane) was detected at 89.8 and 100% of cord and maternal serum samples, respectively. The second and third highest levels detected were p,p'-DDD (1,1-dichloro-2,2-bis(p-chlorophenyl)ethane) and p,p'-DDT, respectively. The ratios between cord and maternal sera for p,p'-DDE, p,p'-DDT, and p,p'-DDD that were less than 1 had high correlation coefficients (ratio = 0.70, r = 0.82 for p,p'-DDE, ratio = 0.62, r = 0.66 for p,p'-DDT, and ratio = 0.79, r = 0.78 for p,p'-DDD). The high correlation coefficients indicate that cord serum levels of DDT compounds could be accurately estimated from maternal serum levels. It can be concluded that cord serum levels of p,p'-DDE, p,p'-DDT, and p,p'-DDD were approximately 70%, 62%, and 79% of maternal serum levels, respectively. Furthermore, our findings can be applied in public health to monitor and evaluate risk among infants from high DDT exposure area.

Rapid decline of persistent organochlorine pollutants in serum among young Swedish males.

To investigate a possible time trend in serum concentrations of persistent organochlorine pollutants (POPs), representative samples of the young (median age 18 years) Swedish male population were investigated in the years 2000 and 2004. Due to their low age, these men were assumed not to have reached steady state of body burdens of POPs, why their serum concentrations were considered to represent ongoing dietary exposure. Serum concentrations of 2,2',4,4',5,5'-hexachlorobiphenyl (CB-153) and 1,1-dichloro-2,2-bis(4-chlorophenyl)-ethylene (p,p'-DDE), two biomarkers of exposure to POPs, were available for 274 and 223 men, respectively, in 2000 and for 200 men in 2004. The percentage of men with CB-153 or p,p'-DDE below the limit of detection (LOD) was significantly higher in 2004 than in 2000 (30% vs. none, p < 0.001 for CB-153 and 65% vs. 6%, p < 0.001 for p,p'-DDE). Moreover, the median serum concentration of CB-153 decreased from 66 ng g(-1) lipid to 19 ng g(-1), corresponding to a yearly decrease of about 26%. The analogous analysis was not done for p,p'-DDE since the median serum concentration in 2004 was below the LOD.

DDE-induced apoptosis in children exposed to the DDT metabolite.

In a preliminary study in children we found a weak positive association between the frequency of apoptosis and the exposure to DDT and DDE (a DDT metabolite). In order to verify this information, more studies were needed with an increased number of children. Thus, the aim of the present work was to see if DDT and its metabolites were able to induce apoptosis of PBMC in exposed children. We performed a study in children living in three communities located in southern Mexico. During the year 2003, we studied a total of 61 healthy children; and during the year 2004, 57 children from the same communities were assessed. Apoptosis frequencies in PBMC in these children ranged from 0.10% to 8.30% during 2003 and from 0.12% to 16.20% during 2004, and although we detected exposure to DDT, DDD and DDE, significant association with apoptosis frequencies was found only with DDE blood levels (p=0.010 and 0.040 for 2003 and 2004 respectively). DNA damage and oxidative DNA damage were also studied in 2004 using the comet assay. The association between exposure to DDT or DDE and DNA damage was significant (p=0.004 and p=0.005 respectively), but the association between DDT or DDE and oxidative DNA damage and that of oxidative damage and apoptosis were not significant. Taking into account that DDE is the most persistent metabolite, it would be important to assess the effects of this DDE-induced apoptosis of PBCM in children living in areas where DDT was sprayed.

[Study on serum organochlorines pesticides (DDTs) level, CYP1A1 genetic polymorphism and risk of breast cancer: a case control study].

OBJECTIVE: To study the potential effect of gene-environment interaction between CYP1A1 and serum dichlorodiphenyldichloroethane (DDT) levels on the risk of breast cancer in women, in China. METHODS: A case-control study was conducted. From Dec. 2003 to Sep. 2004, 104 women with histologically confirmed breast cancers and 154 noncancerous controls from a community were enrolled in this study. Risk factors information of breast cancer was investigated by a questionnaire. Serum p, p'-dichlorodiphenyldichloroethane (p, p'-DDT) and 1, 1-dichloro-2, 2-bis (p-chlorophenyl) ethylene (p, p'-DDE) levels were tested by GC-ECD. CYP1A1 m2 gene type was tested by allele special-PCR method. RESULTS: Serum DDT levels of case and control were (36.90 +/- 79.41) ng/ml and (50.60 +/- 150.70) ng/ml respectively. Serum 1, 1-dichloro-2, 2-bis (p-chlorophenyl) ethylene (p, p'-DDE) levels of case and control were (7.43 +/- 11.10) ng/ml and (8.96 +/- 11.30) ng/ml respectively. No statistically significant differences were found between the two groups with geometric mean t-test (P > 0.05). Compared with women who had homozygous wild-type CYP1A1 m2 genotype, significantly increased risks of breast cancer were found for women with the CYP1A1 m2 homozygous variant genotype [odds ratio (OR) = 2.61, 95% confidence interval (CI): 1.00 - 6.80]. Among premenopausal women, compared with women with homozygous wild-type of CYP1A1 genotype (Ile/Ile) and low serum DDT level (DDT serum level < or = 42.93 ng/ml), women with at least one variant allele of CYP1A1 m2 genotype and high serum DDT level (DDT serum level > or = 42.93 ng/ml) had higher risk of breast cancer (OR = 4.35, 95% CI: 1.140 - 16.950). CONCLUSIONS: CYP1A1 m2 genetic polymorphism was associated with increased risk of female breast cancer while DDT exposure might have increased the risk of breast cancer among premenopausal women with CYP1A1 m2 variant genotype.

The association between organochlorine and thyroid hormone levels in cord serum: a study from northern Thailand.

It is now known that many organochlorines (OCs) act as endocrine disruptors, causing harmful effects on wildlife and humans. Several field and laboratory animal studies have reported that OCs cause adverse effects on thyroid hormone status. However, data regarding their effects on thyroid hormone status in humans are inconclusive. Because a developing fetus is especially sensitive to hormonal disruption by exposure to OCs, the adverse health effects on infants are of concern. The present study aimed to investigate the association between OC levels in maternal and cord serum, and the association between OC and thyroid hormone levels in cord serum. The study was performed with 39 mother-infant pairs from Mae Rim District of Chiang Mai Province, northern Thailand, who had normal delivery and full term gestation. Maternal blood was collected for measuring OCs and total lipids. Umbilical cord blood was collected for measuring OCs, total lipids, and thyroid hormones, including total thyroxine (TT(4)), free thyroxine (FT(4)), and thyroid stimulating hormone (TSH). 1,1-dichloro-2,2-di(4-chlorophenyl)ethylene (p,p'-DDE) had the highest level in all serum samples with a geometric mean of 1,191 ng/g lipids in maternal serum and 742 ng/g lipids in cord serum. The second highest level was that for 1,1,1-trichloro-2,2-di(4-chlorophenyl)ethane (p,p'-DDT), followed by 1,1-dichloro-2,2-di(4-chlorophenyl)ethane (p,p'-DDD). Levels of p,p'-DDE, p,p'-DDT, p,p'-DDD, and dieldrin in maternal serum were positively associated with levels in cord serum (r = 0.86, 0.77, 0.66, and 0.60, respectively; P<0.001). The important findings were that cord serum TT(4) levels were negatively associated with cord serum levels of p,p'-DDE (r = -0.37, P = 0.024), p,p'-DDT.3 (r = -0.33, P = 0.048), and 1,1-dichloro-2-(2-chlorophenyl)-2-(4-chlorophenyl)ethylene (o,p'-DDE) (r = -0.76, P = 0.019). These results therefore suggest that exposure to DDT and its metabolites during fetal development may cause some effects on thyroid hormonal status in infants.

Rapidly progressing high o,p'DDD doses shorten the time required to reach the therapeutic threshold with an acceptable tolerance: preliminary results.

INTRODUCTION: It has been reported that the therapeutic threshold of mitotane, plasma level above 14 microg/ml, is achieved within 3-5 months after o,p'DDD treatment initiation in patients with adrenocortical carcinoma (ACC). OBJECTIVE AND DESIGN: We evaluated pharmacokinetic and tolerance of a high-dose schedule of pure o,p'DDD treatment given in 500-mg tablets of mitotane (Lysodren, Bristol-Myers Squibb, HRA Pharma, Paris, France) in four patients with ACC and two patients with Cushing's syndrome-related endocrine tumours. It was administered at a starting dosage of 3 g/day, which was rapidly increased to 6-9 g/day within 2 weeks according to digestive tolerance and then adjusted according to tolerance and plasma o,p'DDD monitoring. Patients were followed up until they reached the therapeutic threshold of mitotane, and toxicity was recorded. A relationship between o,p'DDD dose and plasma level was sought. RESULTS: The highest starting dosage given ranged between 6 and 9 g a day, during the first two weeks. The daily maintenance dose ranged 4.5-9 g during the next 2 weeks and 3-9 g by the second month of treatment. The therapeutic threshold was reached in all four patients who received o,p'DDD treatment for at least 1 month. Among these four patients, the toxic threshold (plasma mitotane level > 20 microg/ml) was even reached at 6 weeks of therapy in three patients. Grade 1, 2 or 3 toxicity was observed in 3, 2 and 1 patients, respectively. Toxicity resolved after reduction or discontinuation of o,p'DDD therapy. A significant linear correlation was found between plasma mitotane dose and plasma level. CONCLUSIONS: These results suggest that a high-dose o,p'DDD therapeutic schedule is feasible with an acceptable toxicity and may shorten the time required to reach the therapeutic schedule from 3-5 months to 4 weeks. These patients require a close follow-up, combining clinical and plasma o,p'DDD level monitoring every second week. A confirmatory study is ongoing.

Environmental pathways of exposure to DDT for children living in a malarious area of Chiapas, Mexico.

Considering that DDT was used for control of malaria vectors in Mexico, and taking into account that the information regarding children in areas exposed to DDT is scarce, we started a research program for the assessment of health effects in children living in DDT sprayed areas. In this first report, we present information about pathways of exposure in two communities with a different history of exposure to DDT. Environmental pathways such as outdoor soils, indoor soils and household dust were assessed comparing a community highly exposed to DDT (HEC) and a community less exposed to DDT (LEC). Also in these communities, a cross-sectional study of 60 children (30 in each community) aged 6--12 years was conducted. Tests included a questionnaire and the measurement of whole blood DDT and DDE. Results show that in children living in the HEC, DDT and DDE mean blood levels were higher (15.9+/-8.2 and 58.2+/-29.2 microg/L) than in the LEC (1.9+/-3.6 and 9.2+/-5.7 microg/L) (P<0.01). Concentrations of DDT, DDE and DDD in indoor soil were higher in the HEC (10.3+/-10; 4.9+/-5.8; and 4.4+/-9.1mg/kg) than in the LEC (0.3+/-0.3; 0.04+/-0.06; and 0.03+/-0.04 mg/kg) (P<0.001). Similar results were obtained for outdoor soils; in the HEC, levels for DDT, DDE and DDD were 3.1+/-3.0; 1.0+/-0.8; and 0.3+/-0.2mg/kg; whereas levels in the LEC were 0.16+/-0.2; 0.02+/-0.03; and 0.02+/-0.03 mg/kg (P<0.001). High concentrations of DDT, DDE, and DDD were obtained in samples of indoor dust collected from the walls in the HEC (17.5+/-10.0; 5.5+/-6.2; and 9.8+/-16.8 mg/kg); levels in the LEC were lower (0.6+/-0.9; 0.07+/-0.1; and 0.05+/-0.07 mg/kg) (P<0.001). We did not find any correlation between blood levels of DDE and total DDT with environmental concentrations but there levels increased in LEC and HEC as the frequency of fish consumption increased (P<0.01).

DDT induces DNA damage in blood cells. Studies in vitro and in women chronically exposed to this insecticide.

In this study, DDT-induced DNA damage on blood cells was analyzed both in vitro and in vivo. Peripheral blood mononuclear cells (PBMC) were isolated from healthy donors and incubated in the presence of three different concentrations (40, 80, and 100 microg/mL) of p,p'-DDT, p,p'-DDE, and p,p'-DDD at three different treatment times (24, 48, and 72 h). Then, DNA damage was assessed by the single-cell electrophoresis assay (comet assay) as well as by flow cytometry detection of hypodiploid cells (DNA content assay). All compounds induced significant DNA damage as shown by the comet assay. Accordingly, cells exposed to DDT, DDE, and DDD showed a significant increase in the percentage of hypodiploid cells compared with untreated PBMC. In agreement with the in vitro data, a significant correlation between blood levels of DDT, DDD, and DDE and DNA damage (comet assay) was found in women with different amounts of environmental exposure. This association remained significant after controlling for nutritional status, smoking habits, alcohol ingestion, and reported exposure to other pesticides. Although the precise biological importance remains to be explained, our results strongly suggest that DDT and its metabolites are able to induce DNA damage in PBMC both in vitro and in vivo.

DDT induces apoptosis in human mononuclear cells in vitro and is associated with increased apoptosis in exposed children.

The aim of the present work was to investigate whether DDT and its metabolites are able to induce apoptosis of human peripheral blood mononuclear cells (PBMC) both in vitro and in vivo. Cells isolated from healthy individuals were incubated in the presence of increasing concentrations of p'p-DDT, p'p-DDE, or p'p-DDD (0-150 microg/mL) for different intervals. Apoptosis was then determined by flow cytometry (DNA cell content analysis) and fluorescence microscopy (Hoechst staining). A significant level of apoptosis was induced by DDT, DDD, and DDE at 80 microg/mL compared to controls, reaching a maximum effect at 100 microg/mL. We began to detect apoptosis at 12h, with a maximum effect at 24h of incubation. These results were confirmed using the TUNEL assay in cells treated with the three compounds tested as well as with o'p-DDT at 100 microg/mL and 24h of incubation. Our data demonstrate that DDT and its metabolites are able to induce apoptosis of human PBMC in vitro. Therefore, we performed a preliminary study in children exposed to this insecticide. When compared to a control population, the exposed children had higher levels of DDT, DDD, and DDE in blood and also had a higher frequency of apoptosis. In the exposed children, a weak positive association was found between the frequency of apoptosis and the exposure to DDT and DDE. Our results showed that more studies are needed in people exposed to DDT, as apoptosis may cause serious public health effects such as immunosuppression.

[Changes in concentrations of organochloride compounds in women from Flix, Tarragona [Spain]]. / Cambios en las concentraciones de compuestos organoclorados en las mujeres de Flix, Tarragona.

The population of Flix (region of Ribera del Ebro, Tarragona) is highly exposed to hexachlorobenzene (HCB) due to the closeness of an electrochemical factory. Although the degree of HCB contamination in this population is still high, concentrations of HCB in the sera of women aged 18-40 years from 1997 to 1999 were 61% lower than those observed in 1994 (4.1 ng/ml vs. 10.6 ng/ml). Concentrations of dichlorodiphenyl dichloroethane (p,p'-DDE) and beta-hexachlorocyclohexane (beta-HCH) also decreased, although the difference was not statistically significant. In contrast, concentrations of polychlorinated biphenyls (PCB) in the period 1997-1999 showed a nonsignificant increase compared with those in 1994.

A comparative study on the reliablility of toxicokinetic parameters for predicting hepatotoxicity of DDT in rats receiving a single or repeated administration.

A comparative study on the reliability of toxicokinetic parameters for predicting hepatotoxicity was conducted in male F344 rats receiving a single (106 mg/kg by gavage) or 7-day repeated (1000 ppm in feed, 97 mg/kg/day) administration of p,p'-DDT. DDT was selected as the test substance because it is known as a hepatotoxic agent and its metabolic pathway is well documented. Concentrations of DDT and its metabolites (DDE and DDD) in the plasma, brain, and liver were measured at various time intervals during the study and the results were compared with the area under the concentration-time curve (AUC) in relation to hepatotoxic response. Increases in the absolute and relative (ratio to body weight) liver weights were observed as a typical toxic response after a single or repeated exposure to DDT. The coefficient (R2) of correlation between the increases in the relative liver weight and the concentrations or AUC of DDT and its metabolites in the plasma and liver was estimated. The values of R2 between the relative liver weight and AUC of DDT or the total DDT (T-DDT) in the plasma and liver were found to be more consistent and higher than those with their concentrations in the repeated dose study. In addition, the R2 values in correlation with their AUCs after a single exposure were lower than those in the repeated dose study. These results indicate that the AUC of DDT or T-DDT in the plasma and liver would be more reliable than their concentrations for predicting hepatotoxicity caused by DDT, especially in the repeated dose study.