A case study on the application of an expert-driven read-across approach in support of quantitative risk assessment of p,p'-dichlorodiphenyldichloroethane.

Deriving human health risk estimates for environmental chemicals has traditionally relied on in vivo toxicity databases to characterize potential adverse health effects and associated dose-response relationships. In the absence of in vivo toxicity information, new approach methods (NAMs) such as read-across have the potential to fill the required data gaps. This case study applied an expert-driven read-across approach to identify and evaluate analogues to fill non-cancer oral toxicity data gaps for p,p'-dichlorodiphenyldichloroethane (p,p'-DDD), an organochlorine contaminant known to occur at contaminated sites in the U.S. The source analogue p,p'-dichlorodiphenyltrichloroethane (DDT) and its no-observed-adverse-effect level of 0.05 mg/kg-day were proposed for the derivation of screening-level health reference values for the target chemical, p,p'-DDD. Among the primary similarity contexts (structure, toxicokinetics, and toxicodynamics), toxicokinetic considerations were instrumental in separating p,p'-DDT as the best source analogue from other potential candidates (p,p'-DDE and methoxychlor). In vitro high-throughput screening (HTS) assays from ToxCast were used to evaluate similarity in bioactivity profiles and make inferences toward plausible mechanisms of toxicity to build confidence in the read-across approach. This work demonstrated the value of NAMs such as read-across and in vitro HTS in human health risk assessment of environmental contaminants with the potential to inform regulatory decision-making.

DDT, DDD, and DDE in soil of Xiangfen County, China: Residues, sources, spatial distribution, and health risks.

We collected and analyzed 128 surface soil samples from Xiangfen County for dichlorodiphenyltrichloroethane (DDT), dichlorodiphenyldichloroethane (DDD), and dichlorodiphenyldichloroethylene (DDE). Total DDT concentrations (DDTs; sum of p,p'-DDD, p,p'-DDE, and p,p'-DDT) ranged from ND to 427.81 ng g(-1) (dry weight, dw), with a mean of 40.26 ng g(-1) (dw). Among the three compounds, p,p'-DDD was the most dominant. The DDTs in Xiangfen County soils mainly originated from historical DDT use, but there were also new inputs likely related to dicofol use. The DDTs in Xiangfen County soils were mainly degraded under anaerobic conditions, and direct degradation to DDD was the main degradation route. Regions with relatively high concentrations of DDTs were mainly located in North and South Xiangfen County. In these regions, many soil samples contained p,p'-DDT as the predominant pollutant, suggestive of extensive new inputs of DDT. A health risk assessment revealed that there are no serious long-term health impacts of exposure to DDTs in soil, for adults or children.

DDT and its metabolites alter gene expression in human uterine cell lines through estrogen receptor-independent mechanisms.

Endocrine-disrupting organochlorines, such as the pesticide dichlorodiphenyltrichloroethane (DDT), bind to and activate estrogen receptors (ERs), thereby eliciting estrogen-like effects. Although ERs function predominantly through activation of transcription via estrogen-responsive elements, both ERs, alpha and ss, can interact with various transcription factors such as activator protein-1 (AP-1). Additionally, estrogens may regulate early signaling events, suggesting that the biological effects of environmental estrogens may not be mediated through classic ER (alpha and ss) activity alone. We hypothesized that known environmental estrogens, such as DDT and its metabolites, activate AP-1-mediated gene transactivation through both ER-dependent and ER-independent means. Using two Ishikawa human endometrial adenocarcinoma cell line variants that we confirmed to be estrogen responsive [Ishikawa(+)] and estrogen unresponsive [Ishikawa(-)], we generated stably transfected AP-1 luciferase cell lines to identify the role of an estrogen-responsive mechanism in AP-1-mediated gene expression by various stimuli. Our results demonstrate that DDT and dichlorodiphenyldichloroethane (DDD) were the most potent activators of AP-1 activity; 2,2-bis(p-chlorophenyl) acetic acid failed to activate. Although stimulated in both Ishikawa(+) and Ishikawa(-) cells by DDT and its congeners, AP-1 activation was more pronounced in the estrogen-unresponsive Ishikawa(-) cells. In addition, DDT, DDD, and dichlorodiphenyldichloroethylene (DDE) could also stimulate AP-1 activity in the estrogen-unresponsive human embryonic kidney 293 cells using a different promoter context. Thus, our data demonstrate that DDT and its metabolites activate the AP-1 transcription factor independent of ER (alpha or ss) status.

Associations of dichlorodiphenyltrichloroethane (DDT) 4.4 and dichlorodiphenyldichloroethylene (DDE) 4.4 blood levels with plasma IL-4.

DDT (dichlorodiphenyltrichloroethane) reportedly induces cancer in animals, mimics estrogen activity, induces antiandrogen effects, and impairs Natural Killer (NK) cells and T lymphocyte responses. In this study, the authors attempted to determine associations of DDT, dichlorodiphenyldichloroethylene (DDE), and dichlorodiphenyldichloroethane (DDD) blood levels with several immune parameters in patients occupationally exposed to insecticides. The study subjects were 49 patients who worked as farmers or farmhands in the former German Democratic Republic and who had been occupationally exposed to insecticides for at least 6 mo; 80% of them had been exposed for more than 20 yr. Blood levels of DDT, DDE, DDD, 2,3,4,5,6-pentachlorophenol (PCP), polychlorinated biphenyls (PCBs), hexachlorobenzene (HCB), and gamma-hexachlorocyclohexanes (HCHs) were determined, and blood lymphocyte subpopulations, in vitro responses to mitogens or pooled allogeneic stimulator cells, plasma neopterin, and cytokine and soluble cytokine receptor levels were studied. The majority of patients were contaminated with more than 1 chemical--most commonly DDE, PCBs, and HCB. Linear-regression analysis showed that interleukin-4 (IL-4) plasma levels were associated with plasma levels of DDT 4.4 (p = .0001) and DDE 4.4 (p = .001). The data in this study suggest that PCBs, PCP, HCB, HCHs, DDE, and DDD suppress TH1 cytokines, such as IL-2 and interferon-gamma (IFN-gamma), and induce TH2 cytokines, such as IL-4. The authors hypothesized that clinical symptoms, such as the frequent infections reported by many patients, could be a consequence of these immunological abnormalities.

Vigilancia de la salud en exposiciones a tratamientos DDD en un colectivo de empleados postales / Health surveillance of exposure to DDD treatments in postal workers

Objetivo: Valorar el rendimiento del Cuestionario Sintomático Barcelona, patrón habitual de referencia en nuestra área, para la detección de afectados en operaciones con plaguicidas, en una experiencia de vigilancia de la salud de un colectivo de trabajadores de Correos y Telégrafos, en la que fue utilizado dicho cuestionario. El colectivo controlado fue el de los empleados de la central de Barcelona, con riesgo teórico de exposición a plaguicidas, con motivo de alguna fumigación realizada en su centro de trabajo, en el curso de un período retrospectivo de un año desde la práctica de la vigilancia. Sujetos y métodos: Para la elaboración del censo de trabajadores participantes, la selección de centros a estudiar se llevó a cabo en función de tres criterios: la queja de algún trabajador con motivo de la fumigación, el incumplimiento del período de seguridad del producto y la acumulación de dos tercios de los 13 factores de riesgo deducidos de otros estudios. Para la vigilancia de la salud se utilizó el mencionado cuestionario como medida de cribado, una revisión general posterior a los afectados según el cuestionario y una valoración neurológica final. Resultados: De los 187 trabajadores que contestaron al cuestionario, resultaron afectados 21 (2 graves, 4 menos graves y 15 leves). De los 15 afectados que comparecieron a la prueba clínica, sólo 3 presentaron algún síntoma utilizado como criterio de sospecha de afección. La valoración neurológica de estos 3 trabajadores ha concluido por abandono de los interesados. Conclusiones: El rendimiento del cuestionario, es decir, el valor predictivo positivo, en esta experiencia fue muy bajo; dicho parámetro fue superior en la muestra que surge al aplicar el criterio selectivo de quejas colectivas, frente al de incumplimiento de períodos de seguridad; la predicción no concuerda con la gravedad de la afección detectada, y estos hallazgos no desvirtúan el rendimiento del cuestionario en la experiencia del centro autor del mismo, dado que ambas poblaciones no fueron homogéneas (AU)

Environmentally relevant xenoestrogen tissue concentrations correlated to biological responses in mice.

The effects of xenoestrogens have been extensively studied in rodents, generally under single, high-dose conditions. Using a continuous-release, low-dose system in ovariectomized mice, we correlated the estrogenic end points of uterine epithelial height (UEH) and vaginal epithelial thickness (VET) with concentrations of two organochlorine pesticide isomers in fat and blood. Silastic capsules containing a range of doses of either ss-hexachlorocyclohexane (ss-HCH) or o, p'-dichlorodiphenyltrichloroethane (o,p'-DDT) were implanted subcutaneously, and animals were killed after 1 week. Average blood levels achieved by the various doses were 4.2-620 ng/mL for o,p'-DDT and 5.0-300 ng/mL for ss-HCH. Fat concentrations of o,p'-DDT and ss-HCH correlated linearly to blood levels (o,p'-DDT, r(2) = 0.94; ss-HCH, r(2) = 0.83). Fat concentrations (nanograms per gram of tissue) were higher than blood concentrations (nanograms per milliliter) by 90 +/- 5- and 120 +/- 9-fold (mean +/- SE) for o, p'-DDT and ss-HCH, respectively. The VET ranged from 12 +/- 0.9 microm in controls to 114 +/- 8 microm in treated animals, and was correlated to blood levels of either treatment compound. The UEH ranged from an average of 7.7 +/- 0.3 microm in controls to 26 +/- 2 microm in high-dose o,p'-DDT-treated animals. The UEH was also correlated with ss-HCH concentration, but it plateaued at approximately 11 microm at the highest doses. The lowest blood concentrations that produced statistically significant increases in VET or UEH were 18 +/- 2 ng/mL o,p'-DDT and 42 +/- 4 ng/mL ss-HCH. These values are within the same order of magnitude of blood concentrations found in some human subjects from the general population, suggesting that human blood concentrations of these organochlorines may reach estrogenic levels.

A case of adrenocortical carcinoma associated with recurrence after laparoscopic surgery.

Laparoscopic adrenalectomy has become increasingly popular because of its minimally invasive nature, but guidelines for selection of cases suitable for this surgical procedure have not been established. We report a 52-year-old woman with adrenocortical carcinoma, manifesting as Cushing's syndrome, treated with laparoscopic adrenalectomy. The tumour was removed in toto and had been histologically diagnosed as adrenocortical adenoma. However, the patient developed intra-abdominal peritoneal dissemination of carcinoma 15 months after surgery. Review of the histopathological findings of the resected adrenocortical tumour revealed that the neoplasm met five out of nine histological criteria for adrenocortical malignancy, and was diagnosed as adrenocortical carcinoma. Histopathological examination of the tumour was also consistent with adrenocortical carcinoma. The patient responded extremely well to chemotherapy, including carboplatin, etoposide and o,p'-DDD (1,1-dichlorodiphenyldichloroethane), and a subsequent CT (computed tomography) scan 12 months after the start of chemotherapy demonstrated no evidence of disease. However, the patient developed neurological impairment, including dysarthria, as a side-effect of o, p'-DDD. The patient died of aspiration pneumonia due to a decreased pharyngeal reflex. Postmortem examination revealed no foci of residual carcinoma. This case report emphasizes the importance of excluing possible adrenocortical malignancy in patients considered for laparoscopic adrenalectomy, histopathological diagnosis of adrenocortical malignancy and careful monitoring for neurotoxicity during o,p'-DDD treatment.

Pubertal growth and development and prenatal and lactational exposure to polychlorinated biphenyls and dichlorodiphenyl dichloroethene.

OBJECTIVES: Polychlorinated biphenyls (PCBs) and dichlorodiphenyl dichloroethene (DDE) are ubiquitous toxic environmental contaminants. Prenatal and early life exposures affect pubertal events in experimental animals. We studied whether prenatal or lactational exposures to background levels of PCBs or DDE were associated with altered pubertal growth and development in humans. STUDY DESIGN: Follow-up of 594 children from an existing North Carolina cohort whose prenatal and lactational exposures had previously been measured. Height, weight, and stage of pubertal development were assessed through annual mail questionnaires. RESULTS: Height of boys at puberty increased with transplacental exposure to DDE, as did weight adjusted for height; adjusted means for those with the highest exposures (maternal concentration 4+ ppm fat) were 6.3 cm taller and 6.9 kg larger than those with the lowest (0 to 1 ppm). There was no effect on the ages at which pubertal stages were attained. Lactational exposures to DDE had no apparent effects; neither did transplacental or lactational exposure to PCBs. Girls with the highest transplacental PCB exposures were heavier for their heights than other girls by 5.4 kg, but differences were significant only if the analysis was restricted to white girls. CONCLUSIONS: Prenatal exposures at background levels may affect body size at puberty.

Arctic indigenous women consume greater than acceptable levels of organochlorines.

Exposure to polychlorinated biphenyls and organochlorine pesticides through traditional food resources was examined for Arctic Indigenous women living in two cultural and environmental areas of the Canadian Arctic--one community representing Baffin Island Inuit in eastern Arctic and two communities representing Sahtú Dene/Métis in western Arctic. Polychlorinated biphenyls, toxaphene, chlorobenzenes, hexachlorocyclohexanes, dichlorodiphenyltrichloroethane, chlordane-related compounds and dieldrin were determined in local food resources as normally prepared and eaten. Quantified dietary recalls taken seasonally reflected normal consumption patterns of these food resources by women in three age groups: 20-40 y, 41-60 y and > or = 61 y. There was wide variation of intake of all organochlorine contaminants in both areas and among age groups for the Sahtú. Fifty percent of the intake recalls collected from the Baffin Inuit exceeded the acceptable daily intake for chlordane-related compounds and toxaphene, and a substantial percentage of the intake records for dieldrin and polychlorinated biphenyls exceeded the acceptable or tolerable daily intake levels. Primary contributing foods to organochlorine contaminants intake for the Baffin Inuit were meat and blubber of ringed seal, blubber of walrus and mattak and blubber of narwal. Important foods contributing organochlorine contaminant to the Sahtú Dene/Métis were caribou, whitefish, inconnu, trout and duck. The superior nutritional benefits and potential health risks of traditional food items are reviewed, as are implications for monitoring organochlorine contaminant contents of food, clinical symptoms and food use.

Premature births in California sea lions: association with high organochlorine pollutant residue levels.

Premature pupping in California sea lions has been noted on the breeding islands since 1968. Organochlorine pesticides and polychlorinated biphenyl residues were two to eight times higher in tissues of premature parturient females and pups than in similar tissues of full-term parturient females and pups collected on San Miguel Island in 1970.

Chlorinated hydrocarbon insecticides: recent animal data of potential significance for man.

The environmental persistence of chlorinated hydrocarbon insecticides is posing a serious threat to the survival of several wildlife species. Sublethal effects, completely unrelated to the insecticidal properties of these chemicals, have contributed markedly to impaired reproduction in many species and to toxicity in neonatal animals. Considering the insecticide levels found in man, are these chemicals potentially dangerous to human infants and adults? Of special concern are the potential long-term, subtle effects of low concentrations of insecticides to which many persons are ordinarily exposed. These agents affect both the peripheral and central nervous systems. They markedly elevate hepatic enzyme levels, enhancing the biotransformation of many pharmacological agents as well as interfering with endogenous steroid biosynthesis and degradation. The DDT-like insecticides are potent estrogenic agents and some have shown teratogenic and carcinogenic activity. These aspects are discussed in relation to present levels found in humans and to possible adverse effects on perinatal and adult individuals.