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Problems in testing and risk assessment of endocrine disrupting chemicals with regard to developmental toxicology.

Endocrine disrupting chemicals (EDCs) may affect mammalian development either indirectly (by impairing implantation, placental development, lactation, etc.) or directly, altering the maturation of target tissues. Current regulatory tests for reproductive/developmental toxicity should be carefully evaluated with regard to risk assessment of EDCs, considering hazard identification (are relevant endpoints being assessed?) and dose-response assessment (are sensitive NOEL/dose-response curves being provided?). Many in vitro and in vivo assays for sex steroid disruption are available; provided that the metabolic capacities of the assays are defined, they could be integrated in a sensitive battery for early detection of steroid-disrupting potentials. The screening battery should address further regulatory in vivo tests (e.g. what specific parameters have to be investigated). As regards dose-response, qualitative differences may be observed between lower and higher exposures, showing primary hormone-related effects and frank embryotoxicity, respectively. Other problems concern (a) the identification of critical developmental windows, according to hormone concentrations and/or receptor levels in the developing target tissues; (b) the potential for interactions between chemicals with common mechanism/target (e.g. xenoestrogens); (c) most important, besides sex steroids more attention should be given to other mechanisms of endocrine disruption, e.g., thyroid effects, which can be highly relevant to prenatal and postnatal development.

Animals↗

Accumulation and distribution of dietary arsenic in lake whitefish (Coregonus clupeaformis).

Adult lake whitefish (Coregonus clupeaformis) were fed As contaminated diets at nominal concentrations of 0, 1, 10 and 100 microg As/g food (d.w.) for 10, 30 and 64 days. Liver, kidney, stomach, intestine, pyloric caeca, gallbladder, skin and scales were analyzed for As content. The pattern of As accumulation in fish tissues was influenced by reduced feed consumption beginning on day 45 by fish fed the 100 microg As/g food. Significant As accumulation occurred in all tissues examined from fish exposed to the 100 microg As/g food for 30 days, with the exception of gallbladder. After 30 days of exposure, the highest concentration of As was observed in pyloric caeca of fish fed the 100 microg As/g food. Significant accumulation of As occurred in livers and scales of fish fed concentrations of As as low as 10 microg/g for 30 and 64 days. Muscle, gonad, spleen, gills and bone of lake whitefish fed a control diet for 10 days and 100 microg As/g food for 10, 30 and 64 days were also analyzed for As content. As concentrations increased in gonads, spleen and gills of fish fed the 100 microg As/g food for 30 days. Increased concentrations of As were observed in bone of fish fed the high dose food after each duration of exposure. As concentrations did not increase in muscle of fish after 10, 30 or 64 days of exposure. The following manuscript (Pedlar et al., 2001) documents toxicological effects observed in these fish. Analyses of As in pyloric caeca, intestine, liver and scales are recommended to evaluate the bioavailability of As to freshwater fish in environmental monitoring programs.

Administration, Oral↗

Repeated measurements of organochlorine exposure and breast cancer risk (Denmark).

OBJECTIVE: To prospectively evaluate if repeated measurements of organochlorine exposure provide a more precise measure of breast cancer risk. METHODS: In the Copenhagen City Heart Study (CCHS) participants donated blood twice, in 1976-1978 and 1981 1983. Information on breast cancer risk factors was obtained through standardized questionnaires. A cohort nested case-control study of 155 cases and 274 matched breast cancer-free controls who had participated in both CCHS examinations was conducted. The average serum organochlorine concentration over the course of the two examinations was used, testing a possible association between organochlorine exposure and breast cancer risk. RESULTS: A high serum concentration of p,p'-DDT over the course of the two examinations was associated with a more than three-fold significantly increased risk of breast cancer, and a dose-response relationship was apparent. Furthermore, the risk of breast cancer increased with increasing serum concentrations of PCB congener 118 and 138 and the total amount of DDT isomers (sigmaDDT), but the trends were not significant. CONCLUSION: This study provides new evidence of the adverse effect of some organochlorines on breast cancer risk. Furthermore, repeated assessment of exposure during a relevant time period may provide a more precise risk estimate than a single measurement.

Adult↗

Retrospective study of mercury in raccoons (Procyon lotor) in south Florida.

Museum and recent collections of raccoon hair were used to assess whether temporal or spatial trends existed in MMHg distributions in south Florida. The hypothesis that MMHg in raccoon hair had remained the same since 1947 could not be rejected. Some sampling regions showed increases while others did not. However, large differences existed between sites, amounting to a factor of 20 for raccoons collected during 2000 and during the period prior to 1960 (museum samples). Raccoon feeding behavior and the production of MMHg most probably accounted for the spatial differences. Large differences in MMHg concentrations existed in different tissues ranging in order of hair, liver, kidney, muscle, heart, brain, and blood in their respective ratios to blood: 96:10:6:5:4:2.5:1. Liver Hg is 7% MMHg, while hair Hg is 99% MMHg. These associations appear largely regulated by metabolic processes. Speciation of Hg is very important for gaining an understanding of ecosystem and organism Hg dynamics. Further work is needed to establish whether Se plays a role in Hg sequestration and whether hair Hg is a good surrogate for estimating Hg concentrations in other tissues in south Florida raccoon populations.

Animal Structures↗

Case-control study of PCBs, other organochlorines and breast cancer in Eastern Slovakia.

This case-control study was designed to investigate association between polychlorinated biphenyls (PCBs) and risk of breast cancer in an area of high environmental exposure in the Michalovce district of eastern Slovakia. Incident breast cancer cases from the Michalovce district diagnosed between May 1997 and May 1999 were recruited through the Oncology Department of the District Hospital. A total of 15 individual PCB congeners, 2,2'-bis(4-chlorophenyl)-1,1-dichloroethylene (DDE), 2,2-bis(4-chlorophenyl)-1,1,1-trichloroethane (DDT), and hexachlorobenzene (HCB) were measured in the serum of 24 breast cancer patients and 88 population controls in 1998-1999. The median levels of total PCBs were similar in cases (2586 ng/g of lipid) and controls (2682 ng/g of lipid). Higher serum levels (highest vs. lowest tertile) of total PCBs (odds ratio (OR)=0.42, 95% CI 0.10-1.82, p-for trend=0.31), group 1 congeners (OR=0.37, 95% CI 0.10-1.43, P-for trend=0.02), group 2 congeners (OR=0.32, 95% CI 0.07-1.56, P-for trend=0.60), and group 3 congeners (OR=0.49, 95% CI 0.12-2.04, P-for trend=0.51) were inversely associated with risk of breast cancer. Higher serum levels of DDE (OR=3.04, 95% CI 0.65-14.3, P-for trend=0.10) were positively associated with risk of breast cancer, while there was no association for DDT (OR=1.19, 95% CI 0.27-5.23, P-for trend=0.68), and an inverse association for HCB (OR=0.45, 95% CI 0.06-3.19, P-for trend=0.67). While generally not statistically significant, PCB and HCB levels were inversely associated with risk of breast cancer in this highly exposed population. DDE, but not DDT, was positively associated with risk.

Body Burden↗

[10 years of observation by public health offices in Baden-Württemberg--assessment of human biomonitoring for mercury due to dental amalgam fillings and other sources].

Since 1992, in Baden-Württemberg, ten-year old children have been surveyed in the project "Sentinel Health Departments" to study their exposure to environmental pollutants and possible health effects. In the four study areas 1200 children have been investigated every year initially, since 1996 every second year. The data for mercury in body fluids are reported here. The decrease in the body burden of mercury as a result of the declining usage of dental amalgam fillings, was been verified. In 1992/93, of all the children who had been surveyed, the 95 percentile for the body burden of mercury was 3.1 microg/l and in 2000/01 1.35 microg/l. Also to be discussed is the reason why mercury-based cosmetic ointments seriously exceed the HBM-II-intervention-value. Because of using these ointments, concentrations of mercury in urine up to 1400 microg/l were found. A study within the project "Sentinel Health Departments" compared the concentrations of mercury in the urine of adults with those in blood and salvia. The results support the opinion that mercury in urine is appropriate for estimating the mercury uptake from dental amalgam fillings. It can be assumed that these results reflect the situation in the entire Federal Republic of Germany. The ten years' experience confirms that the concept of the "Sentinel Health Departments" is excellently suited to obtain data relevant for environmental health of children. Environmental health protection and the essential gathering of data for future health observation in Baden-Württemberg.

Adult↗

The environment and male fertility: recent research on emerging chemicals and semen quality.

Scientific and public concern about the potential risk of environmental chemicals to male reproductive health has been heightened by reports of downward trends in semen quality, as well as increased rates of developmental urogenital tract anomalies and testicular cancer. Of particular concern is whether some contemporary-use environmental chemicals alter semen quality. Specific toxicants of interest include phthalates and pesticides, as well as polychlorinated biphenyls (PCBs). The human data on the relationship of semen quality with phthalate and pesticide exposure are limited and do not currently allow for a definitive conclusion on whether adult exposure, at background environmental levels, alters semen quality. However, the epidemiologic data support an inverse association of PCBs with reduced semen quality, specifically reduced sperm motility. The associations found were generally consistent across studies despite a range of PCB levels. In addition to the chemicals discussed, there are additional classes of chemicals that require further study on their relation with human semen quality.

Age Factors↗

Predictive value of human biomonitoring in environmental medicine: experiences at the outpatient unit of environmental medicine (UEM) of the University Hospital Aachen, Germany.

There is little data on the distribution of biomonitoring parameters in patients at outpatient Units of Environmental Medicine (UEM). We evaluated the biomonitoring parameters of 646 UEM outpatients from our University Hospital 1988-1998. Few patients were exposed to specific substances. Data of patients who were not obviously exposed was analysed statistically (geometric mean, standard deviation, median, 95th percentile). Results were compared with reference values in literature. Normal distribution of biomonitoring parameters was rare. 95th percentiles for arsenic, chromium, selenium, zinc, phenol and toluene were below standard, 95th percentiles for copper and mercury above, and 95th percentiles for lead, cadmium, pentachlorophenol, lindane, and beta-hexachlorocyclohexane were within the published range of reference values. Thallium as well as most volatile organic compounds analyzed were below detection levels. Aluminum and fluorine exposure was rarely analysed. In view of these results, it is concluded that the indication for biomonitoring needs to be stringent as levels of biomonitoring parameters are generally not risen in patients of the UEM.

Adolescent↗

PCP in the blood plasma: current exposure of the population in Germany, based on data obtained in 1998.

The fungicidal substance pentachlorophenol (PCP) had been used commonly for wood protection and leather impregnation in Germany until 1989, when this substance was prohibited by law. Hence, the body burden in the general population in Germany has been steadily declining. The reference values (95th percentiles) in blood plasma decreased from 20 micrograms PCP/l in 1991 to 12 micrograms/l in 1996. In 1998 the current exposure in a large residential population was investigated. 623 persons with an average age of 34.6 years (0-62 years) were investigated. For all of them there was neither evidence of occupational contact with PCP nor of the presence of PCP in the residential indoor environment. The mean PCP concentration in the plasma samples was 2.4 +/- 3.9 micrograms/l, the median 1.7 micrograms/l, and the 95th percentile 6.1 micrograms/l, the maximum value was 59.3 micrograms/l. In children and adolescents higher median and 95th percentiles were obtained than in adults (median 2.5 vs. 1.5 micrograms/l and 95th percentile 7.7 vs. 5.9 micrograms/l). All values above 20 micrograms/l were checked again individually: relationships with the level of PCP in household dust could not be detected. In one family leather clothing containing PCP, however, was found to be the cause of unusually high PCP values in the blood. Our investigations confirm a trend observed in recent years: exposure to PCP in the population in Germany decreases steadily and leads to an actualized reference value of 6.1 micrograms PCP/l plasma. In individual cases, however, greatly increased PCP levels in blood can still occur today, for example due to leather clothing treated with PCP.

Adolescent↗

Increased urinary excretion of hydroxyproline in runners training in urban areas.

In this study, the authors investigated urinary excretion of hydroxyproline in 120 subjects to test the hypothesis that physical activity is associated with increased exposure to pollution derived from traffic exhaust. The study population comprised active noncompetitive runners (i.e., 21.1% trained < 2.5 hr/wk, 20% trained for 2.5-5.0 hr/wk, and 54.4% trained > 5 hr/wk) who lived in Genoa, an urban area of Northern Italy. The mean hydroxyproline value (24.39 +/- 8.38 standard deviation] mg/24 hr x m2) in a group of 69 runners who trained in tracks and streets located in downtown Genoa was higher (p < .05) than the mean value recorded in a group of 21 runners (13.33 +/- 2.51 mg/24 hr x m2) who trained mainly in a rural environment of Genoa. The difference was even greater (p < .01) when a third comparable group of 30 nonrunners was considered (mean = 12.54 +/- 3.41 [standard deviation] mg/24 hr x m2). In the urban environment, urinary levels of hydroxyproline were correlated significantly with intensity and frequency of running, but they were unrelated to smoking status.

Adult↗

Unusually high incidence of malignant pleural mesothelioma in a town of eastern Sicily: an epidemiological and environmental study.

In a recent epidemiological study, researchers investigated mortality from malignant pleural neoplasms in Italy, and they detected some geographic clusters of cases of this disease. We found a town located in a volcanic area of eastern Sicily to be of special interest. The residents, some of whom were diagnosed with pleural mesothelioma, had never had any relevant exposure to asbestos during their professional lives. The results of an environmental survey suggested that a possible cause of asbestos exposure was the stone quarries near the town. The products of the quarries contain fibrous amphiboles, which are used widely in the local building industry. These fibrous amphiboles were identified as intermediate phases between tremolite and actinolite. Samples were collected from buildings in the town, and concentrations of amphibole fibers were evaluated. Fibrous phases were detected in 71% of the samples, and fiber concentrations ranged from a few thousand to more than 4 x 10(4) fibers/mg of material. In addition, we conducted a study on the mineral fiber lung burden in a pleural mesothelioma case. Many mineral fibers that were classified as the same tremolite-actinolite fibrous amphibole found in the quarries and in the building materials were detected in the lung tissue. The results suggest that the inhabitants of the town we studied had been exposed for several decades to asbestos fibers that were present in the material extracted from the local stone quarries. The material was subsequently used in the building industry, and this has caused an increased risk of pleural mesothelioma in the area.

Adult↗

Respiratory morbidity among children following renovation of a water-damaged school.

The authors sought to determine whether exposure to molds, resulting from moisture damage in a school, was associated with increased respiratory symptoms and morbidity among schoolchildren and whether the renovation of this building resulted in a decrease in prevalence of respiratory symptoms and morbidity. The study was a follow-up (1-y interval) of children between the ages of 7 and 12 y from two elementary schools in a Finnish suburb. In addition to a questionnaire completed by the parents, the authors assessed the respiratory health of children by examining the health records of a local health center. In the cross-sectional study, the prevalence of symptoms and infections were higher in the exposed group, as were visits to a physician and use of antibiotics. The school was renovated, after which all prevalence decreased and no significant differences remained, except for visits to a physician (according to questionnaire responses). Therefore, moisture damage and exposure to molds increased the indoor air problems of schools and affected the respiratory health of children.

Child↗

Risk of respiratory cancer around a sewage plant in Prato, Italy.

In this study, the authors evaluated the risk of respiratory cancer related to environmental pollutants among a population that resided near a sewage plant in Prato, Italy. Subjects included lung cancer deaths (1987-1996) and incident cases of lung and laryngeal cancers (1987-1994) among residents of Prato. The authors used the mortality or incidence rates for the entire population of Prato (by gender and by 5-yr age group) to calculate the expected cases in each census unit. Data were analyzed and adjusted for an index of social deprivation (Stone test). Among males, the excess risk of lung cancer mortality decreased as distance from the plant increased for 2 time periods (1987-1996 [p = .008] and 1990-1996 [p = .030]) and for lung cancer incidence during 1987-1994 (p = .011). Similar results were obtained when sewage plant workers were excluded from the analysis. A similar, but not statistically significant, trend was observed among female incident lung cancer cases, as well as among male incident laryngeal cancer cases. Despite methodological limitations common to geographic studies, the results were consistent with those previously published on mortality excesses for lung cancer among plant workers under study. The role of environmental pollutants as a risk for respiratory cancer must be further clarified with additional epidemiological studies and an environmental monitoring program.

Aerosols↗