Organochlorine pesticides, oxidative stress biomarkers, and leukemia: a case-control study.

Exposure to pesticides has been linked to an elevated risk of leukemia. The present research aimed to evaluate the relationship between organochlorine (OC) pesticides and biomarkers of oxidative stress in patients with leukemia. This work was conducted on 109 patients with leukemia and 109 healthy controls. The serum concentrations of seven derivatives of OCs including alpha-hexachlorocyclohexane (HCH), beta-HCH, gamma-HCH, 2,4-dichlorodiphenyltrichloroethane (DDT), 4,4-DDT, 2,4-dichlorodiphenyldichloroethylene (DDE), and 4,4-DDE along with acetylcholinesterase (AChE), glutathione peroxidase (GPx), superoxide dismutase (SOD), paraoxonase-1 (PON1), and catalase (CAT) activities as well as total antioxidant capacity (TAC), nitric oxide (NO), protein carbonyl (PC), and malondialdehyde (MDA) levels were measured in all the subjects. Levels of OCs were remarkably higher in patients with leukemia compared with the controls (p<0.05). In addition, levels of SOD, AChE, GPx, PON1, and TAC were remarkably lower in patients with leukemia compared with controls (p<0.05). In contrast, MDA, NO, and PC concentrations were higher in patients with leukemia than in the controls (p<0.05). Moreover, the serum level of 4,4-DDE was negatively associated with GPx activity (p=0.038). Our findings suggest that OCs may play a role in the development of leukemia by disrupting the oxidant/antioxidant balance.

Pesticide exposure and neurodevelopmental outcomes: review of the epidemiologic and animal studies.

Assessment of whether pesticide exposure is associated with neurodevelopmental outcomes in children can best be addressed with a systematic review of both the human and animal peer-reviewed literature. This review analyzed epidemiologic studies testing the hypothesis that exposure to pesticides during pregnancy and/or early childhood is associated with neurodevelopmental outcomes in children. Studies that directly queried pesticide exposure (e.g., via questionnaire or interview) or measured pesticide or metabolite levels in biological specimens from study participants (e.g., blood, urine, etc.) or their immediate environment (e.g., personal air monitoring, home dust samples, etc.) were eligible for inclusion. Consistency, strength of association, and dose response were key elements of the framework utilized for evaluating epidemiologic studies. As a whole, the epidemiologic studies did not strongly implicate any particular pesticide as being causally related to adverse neurodevelopmental outcomes in infants and children. A few associations were unique for a health outcome and specific pesticide, and alternative hypotheses could not be ruled out. Our survey of the in vivo peer-reviewed published mammalian literature focused on effects of the specific active ingredient of pesticides on functional neurodevelopmental endpoints (i.e., behavior, neuropharmacology and neuropathology). In most cases, effects were noted at dose levels within the same order of magnitude or higher compared to the point of departure used for chronic risk assessments in the United States. Thus, although the published animal studies may have characterized potential neurodevelopmental outcomes using endpoints not required by guideline studies, the effects were generally observed at or above effect levels measured in repeated-dose toxicology studies submitted to the U.S. Environmental Protection Agency (EPA). Suggestions for improved exposure assessment in epidemiology studies and more effective and tiered approaches in animal testing are discussed.

Alpha-fetoprotein, carcinoembryonic antigen and beta2-microglobulin in adult population highly exposed to organochlorinated pollutants (PCB, DDE and HCB).

OBJECTIVE: It is aimed to obtain some general information about the prevalence of certain biomarkers in highly exposed population and on the interrelations between their serum level as related to that of some major organochlorines (OCs). METHODS: The level of alpha-fetoprotein (AFP), carcinoembryonic antigen (CEA) and beta2-microglobulin (beta2-MG) as well as that of polychlorinated biphenyls (Σ15PCBs), dichlorodiphenyl-dichloroethylene (DDE) and hexachlorobenzene (HCB) was estimated in 2046 adults (834 males and 1212 females) from highly polluted Eastern Slovakia. RESULTS: Great majority of blood levels was lower than two specific units used for individual markers, while the prevalence of values higher than two specific units of appropriate markers. At the same time, the prevalence of all markers level higher than 2 specific units was highly significantly increasing with of stratified PCBs level quintiles which were also positively related to these of DDE and HCB. Some significant correlations between biomarkers level and age were also observed. CONCLUSIONS: Although from the data obtained within this multipurpose field survey any notable interrelations between AFP, CEA and beta2-MG and some specific diseases and/or malignant processes could not be retrospectively specified, from the data obtained it appears that some of such interrelations cannot be definitely excluded.

Influence of sex, maturity and reproduction on PCB and p,p'DDE concentrations and repartitions in the European hake (Merluccius merluccius, L.) from the Gulf of Lions (N.W. Mediterranean).

The main objective of this work was to establish the influence of sex, maturity and reproduction on the contamination of the demersal fish Merluccius merluccius by organochlorine compounds. Polychlorinated biphenyls (PCBs) and p,p'DDE were quantified in muscle, liver and gonads of female and male hakes collected in the Gulf of Lions in 2004 and 2005. Observed levels appeared higher than the population of the Bay of Biscay and lower than the population of the Thyrrenian Sea. Contaminant fingerprints were roughly constant whatever the studied organ and the hake biological condition. Concentrations varied significantly according to the sex and maturity of hakes. Mature specimens were more contaminated than immature, and males presented higher levels than females. This sex effect can be linked to a lower growth rate of males, and a contaminant elimination during female spawning. Gonadal contamination depends on the importance of lipid content and increases with the maturation degree. Although the main organ of energy and PCB storage is the liver, muscle appears as the main contributor to the gonad contamination.

Association between exposure to persistent organohalogen pollutants and epididymal and accessory sex gland function: multicentre study in Inuit and European populations.

Exposure to persistent organochlorine pollutants (POPs) may have negative impact on male reproductive function. We, therefore, investigated the association between serum levels of POPs and epididymal and accessory sex gland function. Serum levels of CB-153, p,p'-DDE and seminal markers of epididymal [neutral-alpha glucosidase (NAG)], prostatic [prostate specific-antigen (PSA)] and zinc, and seminal vesicle function (fructose) were measured from 135 Swedish fishermen and fertile men from Greenland (n=163), Warsaw, Poland (n=167) and Kharkiv, Ukraine (n=158). Multiple linear regression analyses, adjusting for potential confounders, were employed using both continuous and categorized exposure variables. Both exposure and outcome variables were log transformed. Considering the consistency between models with either continuous or categorized CB-153 levels, negative associations with the activity of NAG were found among Greenlandic men (mean difference 7.0 mU/ejaculate, 95% CI 3.0, 34), and in the aggregated cohort (mean difference 4.0 mU/ejaculate, 95% CI -0.2, 8.0). A positive association was observed between CB-153 and PSA as well as zinc among Kharkiv men. In the Swedish cohort, a negative association was found between CB-153 and fructose. In conclusion, the negative effects of POP on sperm motility, observed in the same study population might partly be caused by post-testicular mechanisms, involving a decreased epididymal function.

Cancer mortality among men occupationally exposed to dichlorodiphenyltrichloroethane.

Several studies have evaluated cancer risk associated with occupational and environmental exposure to dichlorodiphenyltrichloroethane (DDT). Results are mixed. To further inquire into human carcinogenicity of DDT, we conducted a mortality follow-up study of 4,552 male workers, exposed to DDT during antimalarial operations in Sardinia, Italy, conducted in 1946 to 1950. Detailed information on DDT use during the operations provided the opportunity to develop individual estimates of average and cumulative exposure. Mortality of the cohort was first compared with that of the Sardinian population. Overall mortality in the cohort was about as expected, but there was a deficit for death from cardiovascular disease and a slight excess for nonmalignant respiratory diseases and lymphatic cancer among the unexposed subcohort. For internal comparisons, we used Poisson regression analysis to calculate relative risks of selected malignant and nonmalignant diseases with the unexposed subcohort as the reference. Cancer mortality was decreased among DDT-exposed workers, mainly due to a reduction in lung cancer deaths. Birth outside from the study area was a strong predictor of mortality from leukemia. Mortality from stomach cancer increased up to 2-fold in the highest quartile of cumulative exposure (relative risk, 2.0; 95% confidence interval, 0.9-4.4), but no exposure-response trend was observed. Risks of liver cancer, pancreatic cancer, and leukemia were not elevated among DDT-exposed workers. No effect of latency on risk estimates was observed over the 45 years of follow-up and within selected time windows. Adjusting risks by possible exposure to chlordane in the second part of the antimalarial operations did not change the results. In conclusion, we found little evidence for a link between occupational exposure to DDT and mortality from any of the cancers previously suggested to be associated.

Polychlorinated biphenyls and menstrual cycle characteristics.

BACKGROUND: Experimental studies in nonhuman primates provide evidence that low-level exposure to persistent organochlorine pollutants such as polychlorinated biphenyls (PCBs) may affect aspects of their menstrual cycle, including cycle length, regularity, and bleeding duration. Few studies have examined these associations in humans. METHODS: We used data from 2314 pregnant women who participated in the Collaborative Perinatal Project, a cohort study that enrolled pregnant women in the 1960s in 12 centers in the United States. Information about usual (prepregnancy) menstrual cycle length, regularity, bleeding duration, and dysmenorrhea was collected at enrollment, and 11 PCBs and p,p'-DDE (1,1-dichloro-2,2-bis(p-chlorophenyl)ethylene (DDE) were measured in stored blood samples collected during the third trimester of pregnancy. We used multivariate linear and logistic regression to examine the association between organochlorine levels and menstrual cycles, adjusting for demographic factors, cholesterol, and triglycerides. RESULTS: Total PCBs were positively associated with increasing menstrual cycle length (adjusted difference across 5 categories of PCB exposure = 0.7 days, trend-test P value = 0.02). Irregular cycles were slightly more frequent among those in the 2 highest categories of PCB exposure (odds ratio for highest category = 1.5; 95% confidence interval = 0.70-3.3), and there also was some evidence of an association with DDE. The strengths of these associations increased with various exclusions made to decrease potential misclassification of the outcome and the exposures. There was little evidence for associations between DDE or PCBs and bleeding duration, heavy bleeding, or dysmenorrhea. CONCLUSIONS: This study supports experimental studies in monkeys showing an effect of low-dose PCB exposure on menstrual function.

Adipose tissue concentrations of p,p'-DDE and the risk for endometrial cancer.

OBJECTIVE: To evaluate in a case-control study possible risk of endometrial cancer associated with environmental endocrine disruptors. METHODS: We analyzed the adipose tissue concentrations of polychlorinated biphenyls, hexachlorobenzene (HCB), p,p'-dichlorodiphenyl-dichloroethylene (p,p'-DDE), chlordanes, and polybrominated biphenyls in 76 cases with endometrial cancer and 39 controls with benign endometrial hyperplasia. RESULTS: For the different chemicals, odds ratios (ORs) and 95% confidence intervals (CI) were close to unity taking the median concentration among the controls as cutoff value. However, for p,p'-DDE OR = 1.9, 95% CI = 0.8-4.8 was obtained. Additional estrogen replacement therapy yielded in this category OR = 2.3, 95% CI = 0.6-8.6. CONCLUSION: The results suggest an interaction between p,p'-DDE and estrogen replacement drugs in the etiology of endometrial cancer, although no significant associations were found.

Acute infections and environmental exposure to organochlorines in Inuit infants from Nunavik.

The Inuit population of Nunavik (Canada) is exposed to immunotoxic organochlorines (OCs) mainly through the consumption of fish and marine mammal fat. We investigated the effect of perinatal exposure to polychlorinated biphenyls (PCBs) and dichlorodiphenyldichloroethylene (DDE) on the incidence of acute infections in Inuit infants. We reviewed the medical charts of a cohort of 199 Inuit infants during the first 12 months of life and evaluated the incidence rates of upper and lower respiratory tract infections (URTI and LRTIs, respectively), otitis media, and gastrointestinal (GI) infections. Maternal plasma during delivery and infant plasma at 7 months of age were sampled and assayed for PCBs and DDE. Compared to rates for infants in the first quartile of exposure to PCBs (least exposed), adjusted rate ratios for infants in higher quartiles ranged between 1.09 and 1.32 for URTIs, 0.99 and 1.39 for otitis, 1.52 and 1.89 for GI infections, and 1.16 and 1.68 for LRTIs during the first 6 months of follow-up. For all infections combined, the rate ratios ranged from 1.17 to 1.27. The effect size was similar for DDE exposure but was lower for the full 12-month follow-up. Globally, most rate ratios were > 1.0, but few were statistically significant (p < 0.05). No association was found when postnatal exposure was considered. These results show a possible association between prenatal exposure to OCs and acute infections early in life in this Inuit population.

Associations between plasma DDE levels and immunologic measures in African-American farmers in North Carolina.

Experimental studies in rodents demonstrate evidence of immunosuppressive effects of dietary exposure to DDT [2,2-bis((italic)p(/italic)-chlorophenyl)-1,1,1-trichloroethane], but human data pertaining to immunomodulating effects of DDT exposure are limited. In this study we examined the association between the persistent organochlorine breakdown product 1,1-dichloro-2,2,bis(p-chlorophenyl)ethylene p,p'-DDE) and immunologic measures using blood samples in a relatively highly exposed population of farmers in the United States. Levels of serum immunoglobulin A (IgA) and IgG and the prevalence of antinuclear antibodies in relation to plasma p,p'-DDE levels were evaluated in samples from 137 African-American male farmers (30-88 years of age; median, 64 years). Participants were recruited through black churches in four rural counties in eastern North Carolina. Data collection included a telephone interview pertaining to farming practices and health history, and one blood sample was collected from each participant. Linear and logistic regression, adjusting for age, cholesterol, triglycerides, smoking status, and years of any kind of pesticide use, was used to assess the association between immunologic parameters and plasma levels of p,p'-DDE. The median plasma p,p'-DDE concentration was 7.7 microg/L (range, 0.6-77.4 microg/L). There was no association between p,p'-DDE and IgA in any of the models. IgG levels decreased with increasing p,p'-DDE levels, with a statistically significant decrease of approximately 50% in the highest two categories of exposure (greater than or equal to 6.0 microg/L) compared with values of < 3.0 microg/L. Sixteen (12%) were positive for antinuclear antibodies. The prevalence of antinuclear antibodies was somewhat elevated in the highest category of p,p'-DDE exposure (odds ratio, 1.9; 95% confidence interval, 0.32-11.3; for > or = 12.0 microg/L compared with < 3.0 microg/L p,p'-DDE), but this difference was not statistically significant. These analyses provide evidence that p,p'-DDE modulates immune responses in humans.

Dichlorodiphenyldichloroethane burden and breast cancer risk: a meta-analysis of the epidemiologic evidence.

The relationship of dichlorodiphenyltrichloroethane (DDT) exposure and breast cancer risk has received increasing attention since the beginning of the 1990s. Contradicting published results regarding the relationship between body burden levels of p,p'-dichlorodiphenyldichloroethane (p,p'-DDE)--the main DDT metabolite--and breast cancer, we argue that such differences stem from methodologic differences among those studies. We performed a meta-analysis of 22 articles using DerSimonian and Laird's method for random effects models. The Q-statistic was used to identify heterogeneity in the outcome variable across studies. The gradient of p,p'-DDE exposure in epidemiologic studies was homogenized to serum lipid bases (nanograms per gram). The potential for publication bias was examined by means of the Begg's test. We discuss methodologic features of the studies in an attempt to reconcile the findings. The summary odds ratio (OR) for selected studies was 0.97 (95% confidence interval, 0.87-1.09) and the gradient of exposure ranged from 84.37 to 12,948 ng/g. No overall heterogeneity in the OR was observed (chi-squared = 27.93; df = 23; p = 0.218). Neither the study design nor the lack of breast-feeding control or the type of biologic specimen used to measure p,p'-DDE levels were the causes of heterogeneity throughout the studies. Evidence for publication bias was not found (p = 0.253). Overall, these results should be regarded as a strong evidence to discard the putative relationship between p,p'-DDE and breast cancer risk. Nevertheless, the exposure to DDT during critical periods of human development--from conception to adolescence--and individual variations in metabolizing enzymes of DDT or its derivatives are still important areas to be researched in regard to breast cancer development in adulthood.

Organochlorine concentrations in diseased vs. healthy gull chicks from the northern Baltic.

The population decline of the nominate lesser black-backed gull Larus fuscus fuscus in the Gulf of Finland (northern Baltic) is caused by an exceedingly high chick mortality due to diseases. The chick diseases include degeneration in various internal organs (primarily liver), inflammations (mainly intestinal), and sepsis, the final cause of death. The hypothesis of starvation causing intestinal inflammations (leading to sepsis) was tested by attempting to reproduce lesions in apparently healthy herring gull L. argentatus chicks in captivity. The herring gull chicks were provided a similar low food-intake frequency as observed for the diseased chicks in the wild. However, empty alimentary tract per se did not induce the intestinal inflammations and therefore, inflammations seem to be innate or caused by other environmental factors in the diseased lesser black-backed chicks. They had very high concentrations of PCB in their liver; but the concentrations were not significantly higher than those of the healthy herring gull chicks, indicating a common exposure area for both species (i.e. the Baltic Sea). When compared to NOEL and LOEL values for TEQs in bird eggs our TEQ levels clearly exceed most or all of the values associated with effects. Compared with published data on fish-eating waterbirds, the DDE concentrations in the diseased lesser black-backed chicks were well above the levels previously correlated with decreased reproduction, while the residues in apparently healthy herring gulls were below those levels. The DDE/PCB ratio in lesser black-backs was significantly elevated, indicating an increased exposure to DDTs as compared with most other Baltic and circumpolar seabirds. The possible exposure areas of DDT in relation to differential migration habits of the two gull species are discussed.

DDE poisoning in an adult Bald eagle.

A 12-year-old female bald eagle (Haliaeetus leucocephalus) was found in May 1993 on Santa Catalina Island, California (USA), in a debilitated condition, exhibiting ataxia and tremors; it died within hours. On necropsy, the bird was emaciated but had no evidence of disease or physical injury. Chemical analyses were negative for organophosphorus pesticides and lead poisoning. High concentrations of DDE (wet weight basis) were found in the brain (212 ppm), liver (838 ppm), and serum (53 ppm). Mobilization of DDE, from depleted fat deposits, probably resulted in the lethal concentration in the eagle's brain.

Cattle poisoning by a mixture of endosulfan, dieldrin, DDT and DDE.

In late July of 1994 two 11-mo-old Holstein heifers were found dead inside a barn after a break-and-entry into it by several animals. The other animals showed no signs of sickness. The predominant postmortem findings were pulmonary edema and muscular hemorrhage. Chemical analysis found endosulfan, dieldrin, DDT and DDE in the rumen contents of both animals. The owner admitted that a very old bottle of pesticide had been knocked over and consumed by these animals; the lid consisted of plastic tape. The sale of DDT to the public was discontinued in the US on January 1, 1973, and the sale of dieldrin was halted in the US in 1987. This case demonstrates that poisoning by long obsolete farm chemicals still must be considered in differential diagnoses of acute deaths.

Organochlorine and mercury contamination in United Kingdom seals.

In 1988 and 1989 tissue samples were obtained from the grey seal (Halichoerus grypus) population found in the Dee estuary in the north west of England and from harbour seals (Phoca vitulina) from the populations in the Wash and north east Scotland and analysed for mercury and organochlorine compounds. Adult seals from the Dee estuary were highly contaminated with mercury and polychlorinated biphenyls (PCBs), and one animal from the Dee contained traces of dichlorodiphenyltrichloroethane (DDT), suggesting the recent use of this banned pesticide. The levels of hexachlorobenzene in the livers of two Dee seals exceeded those in the blubber, possibly indicating liver malfunction or recent exposure. The same relationship was found for hexachlorobenzene in three specimens from the Wash and, in one of these animals, the liver was also more highly contaminated than the blubber with dieldrin and PCBs. Levels of contamination were lower in seals from the Wash and even lower in animals sampled in Scotland, where only dichlorophenyldichloroethylene, the metabolite of DDT, was routinely detected. The toxicological significance of the results is discussed, particularly in relation to the mortality observed in the seal epizootic of 1988.

Cross-sectional study of a community with exceptional exposure to DDT.

The geometric mean level of total DDT in serum samples (76.2 ng/mL) from 499 persons living downstream from a defunct DDT-manufacturing plant was several times the national geometric mean (15.0 ng/mL). DDE isomers, metabolites of DDT, accounted for an average of 86.7% of total DDT. Total DDT levels increased with age, even when controlled for other independent variables also significantly associated with DDT: race, sex, fish consumption, years of residence, socioeconomic status, alcohol consumption, and serum triglyceride levels. Fish consumption, the second strongest determinant of DDT level, had one third the predictive power of age. Total DDT levels were not associated with specific illness or ill health. However, total DDT levels were positively associated with levels of serum cholesterol, triglyceride, and gamma-glutamyl transpeptidase. The finding that serum DDE levels increase with age suggests that no equilibrium in body burden has been reached or that pharmacokinetics or serum/adipose partition may vary with age.