bluuebunny/crossref_metadata_2025 huggingface dataset:
Predicting regional climate change: living with uncertainty
Authors: Mitchell Timothy D. , Hulme Mike
Published: January 2007

Regional climate prediction is not an insoluble problem, but it is a problem characterized by inherent uncertainty. There are two sources of this uncertainty: the unpredictability of the climatic and global systems. The climate system is rendered unpredictable by deterministic chaos; the global system renders climate prediction uncertain through the unpredictability of the external forcings imposed on the climate system. It is commonly inferred from the differences between climate models on regional scales that the models are deficient, but climate system unpredictability is such that this inference is premature; the differences are due to an unresolved combination of climate system unpredictability and model deficiencies. Since model deficiencies are discussed frequently and the two sources of inherent uncertainty are discussed only rarely, this review considers the implications of climatic and global system unpredictability for regional climate prediction. Consequently we regard regional climate prediction as a cascade of uncertainty, rather than as a single result process sullied by model deficiencies. We suggest three complementary methodological approaches: (1) the use of multiple forcing scenarios to cope with global system unpredictability; (2) the use of ensembles to cope with climate system unpredictability; and (3) the consideration of the entire response of the climate system to cope with the nature of climate change. We understand regional climate change in terms of changes in the general circulations of the atmosphere and oceans; so we illustrate the role of uncertainty in the task of regional climate prediction with the behaviour of the North Atlantic thermohaline circulation. In conclusion we discuss the implications of the uncertainties in regional climate prediction for research into the impacts of climate change, and we recognize the role of feedbacks in complicating the relatively simple cascade of uncertainties presented here.
Palaeoenvironmental evidence for solar forcing of Holocene climate: linkages to solar science
Authors: Chambers Frank M. , Ogle Michael I. , Blackford Jeffrey J.
Published: January 2007

Current concern over ‘greenhouse’ warming and possible human influence upon global climate has been countered by claims that recent advances in solar theory demonstrate a greater role than previously thought for solar forcing in recent climate change. This is still disputed for this century, but new evidence from a range of palaeoenvironmental indicators lends strong support to the notion that not only the long-term (105 to 103 years) climate changes of the Pleistocene but also short-term (101 to 102 years) climate changes in the Holocene may derive in large or small part from solar variability. Evidence from recent research into proxy climate records is reviewed and set in the context of recent advances elsewhere in studies of late Quaternary palaeoenvironments and in solar science.
From GCMs to river flow: a review of downscaling methods and hydrologic modelling approaches
Authors: Xu Chong-yu
Published: January 2007

The scientific literature of the past decade contains a large number of reports detailing the development of downscaling methods and the use of hydrologic models to assess the potential effects of climate change on a variety of water resource issues. This article reviews the current state of methodologies for simulating hydrological responses to global climate change. Emphasis is given to recent advances in climatic downscaling and the problems related to the practical application of appropriate models in impact studies. Following a discussion of the advantages and deficiencies of the various approaches, challenges for the future study of the hydrological impacts of climate change are identified.
The sun-climate relationship in recent centuries: a review
Authors: Waple Anne M.
Published: January 2007

There has been confirmation in the last two decades, through instrumental measurements onboard satellites, that the ‘solar constant’ does, as has long been hypothesized, vary over different timescales and with identifiable periodicities. This being the case, it is necessary to explore how these variations play a role in terrestrial climate change. While there is no consensus as to the best method for estimating past variations in solar output, it seems likely that over the last 500 years the sun has played a role in the changing climate. However, there is little evidence to suggest that changes in irradiance are having a large impact on the current warming trend.
The weather generation game: a review of stochastic weather models
Authors: Wilks D. S. , Wilby R. L.
Published: January 2007

This article reviews the historical development of statistical weather models, from simple analyses of runs of consecutive rainy and dry days at single sites, through to multisite models of daily precipitation. Weather generators have been used extensively in water engineering design and in agricultural, ecosystem and hydrological impact studies as a means of in-filling missing data or for producing indefinitely long synthetic weather series from finite station records. We begin by describing the statistical properties of the rainfall occurrence and amount processes which are necessary precursors to the simulation of other (dependent) meteorological variables. The relationship between these daily weather models and lower-frequency variations in climate statistics is considered next, noting that conventional weather generator techniques often fail to capture wholly interannual variability. Possible solutions to this deficiency - such as the use of mixtures of slowly and rapidly varying conditioning variables - are discussed. Common applications of weather generators are then described. These include the modelling of climate-sensitive systems, the simulation of missing weather data and statistical downscaling of regional climate change scenarios. Finally, we conclude by considering ongoing advances in the simulation of spatially correlated weather series at multiple sites, the downscaling of interannual climate variability and the scope for using nonparametric techniques to synthesize weather series.
Hyperspectral remote sensing for estimating biophysical parameters of forest ecosystems
Authors: Treitz Paul M. , Howarth Philip J.
Published: January 2007

Remote sensing has demonstrated wide applicability in the area of estimating and mapping forest physical and structural features. Focus in recent years has been directed towards measuring the biophysical/physiological character of forest ecosystems in order to estimate and predict forest ecosystem health and sustainability. The following reviews the relationship between forest condition and reflectance; remote-sensing measurements (and derivatives) that provide biophysical/physiological information; and the potential of hyperspectral sensors in the measurement of these parameters.
Forest ecosystem simulation modelling: the role of remote sensing
Authors: Lucas Neil S. , Curran Paul J.
Published: January 2007

In recent years forest ecosystems have come under increasing pressure from environmental changes such as global warming and the impacts of pollution. Recent research has indicated that computer-simulation models driven by remotely sensed estimates of key variables may be used to assess the spatial impact of global environment changes on forest processes. This article begins with a discussion of key issues related to driving such models with remotely sensed estimates of these key variables. The article then outlines an investigation that examined whether a general ecosystem simulation model (FOREST-BGC), driven by remotely sensed and meteorological data, could be used to estimate forest processes for a Sitka spruce ( Picea sitchensis) plantation in mid-Wales.
Quaternary environmental change in New Zealand: a review
Authors: Newnham R. M. , Lowe D. J. , Williams P. W.
Published: January 2007

The discovery that orbital variations are the driving force behind Quaternary climate change provides an impetus to set local and regional records of environmental change into the global context, a principle that has been strongly embraced by Quaternary scientists working in New Zealand. Their major achievements and significant current initiatives are reviewed here. The importance of the New Zealand Quaternary stems from its geographical context: a climatically sensitive, remote oceanic, southern location spanning 17 degrees of the mid-latitudes; an obliquely convergent plate boundary setting resulting in a high mountain range athwart the prevailing westerlies, active volcanism, a youthful and dynamic landscape, and mountains high enough to maintain glaciers today; and a remarkably short prehistory. The resultant records show marked environmental changes due not only to climatic oscillations but also to vigorous, active tectonism and volcanism. The Taupo Volcanic Zone, containing the world's strongest concentration of youthful rhyolitic volcanoes, has produced at least 10 000 km3of magma in the last 2 Ma. Climatic interpretations of records from marine sediments in the New Zealand region, together with several long sequences of alternating marine and terrestrial sediments, indicate broad synchrony with Northern Hemisphere events (within limitations of dating), although there are differences in detail for shorter-term climatic events. It is not yet certain that glacial advances coincided precisely with those in the Northern Hemisphere or were of similar duration. Late Cainozoic glaciation commenced c. 2.6-2.4 Ma but the record of glacial deposits is fragmentary and poorly dated except for the most recent events. The Last (Otira) Glaciation, from c. 100-10 ka, was characterized by at least five glacial advances including during the Last Glacial Maximum from 25 to 15 ka, when snowlines fell by 600-800 m. New Zealand evidence for cooling during the Younger Dryas stade is equivocal whilst isotopic records from speleothems, and other data, indicate warmer and wetter conditions from 10-7 ka, broadly conforming with records from mid-latitude Northern Hemisphere locations. Future advances will require sampling at shorter timescales, improvements in the accuracy and precision of existing dating methods and the development of new ones, extension of palaeoecological techniques to cover the full potential of new Zealand's diverse biota, and a stronger emphasis on quantification of palaeoclimatic parameters.
Neighborhood Structural Qualities, Adolescents’ Perceptions of Neighborhoods, and Latino Youth Development
Authors: Plunkett Scott W. , Abarca-Mortensen Sandra , Behnke Andrew O. , Sands Tovah
Published: January 2007

The purposes of this research brief were to examine (a) whether youth reports of neighborhood qualities were significantly related to census data at the block group, measuring the same structural qualities and (b) whether the structural qualities were related to youth development either directly or indirectly through youth perceptions. Data were collected from three sources: self-report surveys, school records, and the 2000 U.S. census. A nonrandom sample of 534 Latino students from one high school in Los Angeles was used. Correlations and structural equation modeling (SEM) demonstrated that youth reports of neighborhoods were significantly related to the structural qualities. SEM demonstrated that the structural qualities were indirectly related to all four adolescent outcomes (i.e., self-esteem, self-efficacy, academic aspirations, grades) via adolescents’ perceptions.
Correlations among tumor types in mouse cancer bioassays: liver adenomas, liver carcinomas, leukemias and lymphomas
Authors: Linkov Igor , Polkanov Michael , Shagiakhmetov Azat , Wilson Richard , Gray George M.
Published: January 2007

In an examination of rodent bioassays Young and Gries [Young S.S., and Gries C.L. Exploration of the negative correlation between proliferative hepatocellular lesions and lymphoma in rats and mice—establishment and implications. Fundam. Appl. Toxicol. 1984: 4: 632-640] and Haseman et al. [Haseman J.K., et al. Body weight-tumor incidence correlations in long-term rodent carcinogenicity studies. Toxicol. Pathol. 1997: 25: 256-263] noticed that there is a negative correlation (anticorrelation) between development of liver tumors and leukemia or lymphomas. If an animal has a lymphoma or leukemia it is less likely to develop liver tumors. These studies noted that this applies to several strains of animals. The anticorrelation appeared in control animals. In this paper we study this anticorrelation in the quarter of a million rodents exposed in the Carcinogenesis Bioassay Database System (CBDS) database of the National Toxicology program in both control and dosed animals. We failed to completely replicate Young and Gries or Haseman et al. However, when benign liver tumors (adenomas or nodules) and malignant liver tumors (carcinomas) are considered separately AND different leukemia and lymphoma types are considered, a strong anticorrelation appears. We identify survival and the time period (in years) during which the bioassay was completed as an important factor in interpreting correlations and anticorrelations. Differences between liver adenomas and carcinomas and lymphoma types contribute to a more general question of grouping of the individual tumor types. In our classification scheme (originally developed about 1986 by Dr. Bailar) an effort is made to distinguish benign and malignant neoplasms, while other investigators group all tumors at a specific site. For many analyses liver adenomas and carcinomas have been lumped together. This is because it is suspected that the diagnoses by pathologists may not distinguish, or ignore the (benign) adenoma when a (malignant) carcinoma is present. Possible biological differences in tumor mechanisms may require separate evaluation of these tumors with all the dangers of “pathologist bias” that this introduces.
Comparative in vitro percutaneous absorption of nonylphenol and nonylphenol ethoxylates (NPE-4 and NPE-9) through human, porcine and rat skin
Authors: Monteiro-Riviere Nancy A. , Van Miller John P. , Simon Glenn , Joiner Ronald L. , Brooks James D. , Riviere Jim E.
Published: January 2007

The purpose of this study was to assess the percutaneous absorption of nonylphenol (NP) and the nonylphenol ethoxylates, NPE-4 and NPE-9, in human, porcine and rat skin. In vitro studies with the NPEs were conducted for 8 h in flowthrough diffusion cells using topical solutions of 0.1, 1.0 and 10% in PEG-400 or 1% in water (NPE-9 only). NP absorption was assessed as a 1% solution in PEG-400. All compounds were 14C ring-labeled and radioactivity in perfusate was monitored over time. Skin deposition was measured at the termination of the experiment. Absorption into perfusate and total penetration (compound absorbed plus compound sequestered in skin) were calculated. Absorption of NPE-4, NPE-9 and NP was similar across all species at less than 1% of the applied dose over 8 h. Penetration was generally below 5% of applied dose, the majority located in the stratum corneum. In all species and for both NPEs, the fraction of dose absorbed was highest for the lowest applied dose. Absorptions expressed as actual mass absorbed over 8 h were similar (approximately 0.3 μg/cm2) across all concentrations. Penetration, but not absorption, was greater from a water vehicle compared to a PEG-400 vehicle, particularly in rat skin. These studies suggest that NP, NPE-4 and NPE-9 were minimally absorbed across skin from all three species. Fractional absorption was concentration-dependent, making the actual absorbed flux constant across all doses.
Breast-feeding exposure of infants to selected pesticides: a public health viewpoint
Authors: Pohl Hana R. , Tylenda Carolyn A.
Published: January 2007

In this paper, we provide an overview of the public health implications of exposure to some pesticides via breast milk and provide health-based guidance. The presence of organochlorine pesticides in breast milk has been documented in many studies around the world. Included in our review are aldrin/dieldrin, chlordane, 1,1,1-trichloro-2,2-bis( p-chlorophenyl)ethane (DDT)/1,1-dichloro-2,2-bis( p-chlorophenyl)ethylene (DDE), endrin, hexachlorobenzene (HCB), and hexachlorocyclohexane (HCH). Toxicological and environmental data on these chemicals are compiled in toxicological profiles published by the Agency for Toxic Substances and Disease Registry (ATSDR). Based on the data, ATSDR derives chemical-specific minimal risk levels (MRLs) that assist in evaluating public health risks associated with exposure. MRLs are health-based guidance values designed to protect the most sensitive populations, including breast-fed infants. We compare MRLs and projected intakes from the breast milk for the listed pesticides, explore the possibilities of toxicological interactions, and provide health-based recommendations.
Effects of short-term JP-8 jet fuel exposure on cell-mediated immunity
Authors: Harris David T. , Sakiestewa Debbie , Robledo Raymond F. , Young R. Scott , Witten Mark
Published: January 2007

The U.S. Air Force has implemented the widespread use of JP-8 jet fuel in its operations, although a thorough understanding of its potential effects upon exposed personnel is unclear. Exposure to environmental toxicants such as JP-8 may have significant effects on host physiology. Jet fuel exposure has been shown to cause human liver dysfunction, abnormal electroencephalograms, shortened attention spans, and decreased sensorimotor speed. Previous studies have shown that short-term, low-concentration JP-8 exposure had significant effects on the immune system; e.g., decreased viable immune cell numbers, decreased immune organ weights, and loss of immune function that persisted for extended periods of time (i.e., up to 4 weeks post-exposure). In the current study, an in-depth analysis of the effects of JP-8 exposure on cellular immunity was performed. Short-term (7 days, 1 h/day), low-concentration (1000 mg/m3) exposures were conducted in mice, and T cell and natural killer (NK) cell functions were analyzed 24 h after the last exposure. The exposure regimen was found to almost completely ablate NK cell function, as well as significantly suppress the generation of lymphokine-activated killer (LAK) cell activity. Furthermore, JP-8 exposure suppressed the generation of cytotoxic T lymphocyte (CTL) cells from precursor T cells, and inhibited helper T cell activity. These findings demonstrate that JP-8 jet fuel exposure has significant detrimental effects on immune functions of exposed individuals. JP-8 jet fuel should be considered a potential and significant immunotoxicant. Chronic exposure to JP-8 may have serious implications to the long-term health of exposed individuals.
The neurotoxic etiology of the autistic spectrum disorders: a replication study
Authors: Edelson Stephen B. , Cantor David
Published: January 2007

Although it has been recognized that autism is a disorder due to dysfunctional central nervous system functioning, a model that can account for the diversity of the symptoms in the syndrome and the concordant anomalies in metabolic functioning, in a sample of 20 autistic individuals, Edelson and Cantor [Edelson S.B., and Cantor D.S. Autism: xenobiotic influences. Toxicol Ind Health 1998: 14 (6): 799-811.] demonstrated a body burden of neurotoxicants in over 90% of these individuals with 100% of these individuals demonstrating impaired liver detoxication processes. This current study examined an independent sample of 39 autistic individuals and was able to replicate the general findings of Edelson and Cantor. We further evidence the genetic and environmental aspects of this hypothetical process and believe the immune system injury secondary to the immunotoxins causes “activation” of the immune system leading to the production of autoantibodies against haptens (brain proteins attached to chemical molecules), and the subsequent damage as part of the process of neurotoxicity in the autistic spectrum. This process has as its final pathway one of free radical generation and molecular injury. This paper can not go into the complex details of this process at this time. All of the above leads to a spectrum of neurodevelopment dysfunction demonstrated as autism.
Substance P as prophylaxis for JP-8 jet fuel-induced immunotoxicity
Authors: Harris David T. , Sakiestewa Debbie , Titone Dominic , Robledo Raymond F. , Young R. Scott , Witten Mark
Published: January 2007

Previous studies have shown that short-term, low-concentration JP-8 exposure had significant effects on the immune system that persisted for extended periods of time. It was found that administration of aerosolized substance P (SP) was able to protect exposed animals from JP-8-induced immune changes, whereas administration of SP antagonists compounded the deleterious effects of jet fuel exposure. Thus, SP administration appears to be a relatively simple and efficient means to reverse the immunotoxicity due to hydrocarbon exposure. In the current study, aerosolized SP was analyzed for its potential prophylactic ability to counteract JP-8-induced immunotoxicity. It was observed that concentrations as low as 1 nM were effective in ameliorating the effects of JP-8 exposure on the immune system. SP administered before JP-8 exposure could prophylactically protect both the spleen and thymus from significant organ weight loss, but could not completely restore immune cell numbers to normal, baseline levels. Furthermore, SP treatment could be delayed as long as 1 h postexposure and reverse the effects of jet fuel exposure on immune organ weight loss and immune cell recovery. Significantly, SP could be given 15 min pre-JP-8 exposure but neither 1 nor 6 h pre-JP-8 exposure, and prevent immune dysfunction as measured in mitogenesis assays. However, SP could be delayed up to 6 h post-JP-8 exposure and still almost completely restore immune function. Thus, SP appears able to both prevent and reverse the immunotoxicological effects associated with JP-8 exposure. These results also provide insight into the manner in which JP-8 jet fuel mediates its effects on the immune system.
Jet fuel-induced immunotoxicity
Authors: Harris David T. , Sakiestewa Debbie , Titone Dominic , Robledo Raymond F. , Young R. Scott , Witten Mark
Published: January 2007

Chronic exposure to jet fuel has been shown to cause human liver dysfunction, emotional dysfunction, abnormal electroencephalograms, shortened attention spans, and to decrease sensorimotor speed (3-5). Exposure to potential environmental toxicants such as jet fuel may have significant effects on host systems beyond those readily visible (e.g., physiology, cardiology, respiratory, etc.), e.g., the immune system. Significant changes in immune function, even if short-lived, may have serious consequences for the exposed host that may impinge affect susceptibility to infectious agents. Major alterations in immune function that are long lasting may result in an increased likelihood of development and/or progression of cancer, as well as autoimmune diseases. In the current study mice were exposed 1 h/day for 7 days to a 1000-mg/m3 concentration of aerosolized jet fuel obtained from various sources (JP-8, JP-8+100 and Jet A1) and of differing compositions to simulate occupational exposures. Twenty-four hours after the last exposure the mice were analyzed for effects on the immune system. It was observed that exposure to all jet fuel sources examined had detrimental effects on the immune system. Decreases in viable immune cell numbers and immune organ weights were found. Jet fuel exposure resulted in differential losses of immune cell populations in the thymus. Further, jet fuel exposure resulted in significantly decreased immune function, as analyzed by mitogenesis assays. Suppressed immune function could not be overcome by the addition of exogenous growth factors known to stimulate immune function. Thus, short-term, low-concentration exposure of mice to aerosolized jet fuel, regardless of source or composition, caused significant deleterious effects on the immune system.
Elevated oxidative stress in skin of B6C3F1 mice affects dermal exposure to metal working fluid
Authors: Shvedova Anna A. , Kisin Elena , Kisin Julia , Castranova Vincent , Kommineni Choudari
Published: January 2007

Metal working fluids (MWFs) are widely used in industry for metal cutting, drilling, shaping, lubricating, and milling. Potential for dermal exposure to MWFs exists for a large number of men and women via aerosols and splashing during the machining operations. It has been reported earlier that occupational exposure to MWFs causes allergic and irritant contact dermatitis. Previously, we showed that dermal exposure of female and male B6C3F1 mice to 5% MWFs for 3 months resulted in accumulation of mast cells and elevation of histamine in the skin. Topical exposure to MWF also resulted in elevated oxidative stress in the liver of both sexes and the testes in males. The goal of this study was to evaluate the interaction between oxidative stress in the skin and topical application of MWF. Oxidative stress in skin of B6C3F1 mice of both sexes was generated by intradermal injection of the hydrogen peroxide (H2O2) -producing enzyme, glucose oxidase with polyethylene glycol (GOD+PEG). In mice given GOD+PEG, topical treatment with MWF (200 l, 30%, for 1, 3, or 7 days) resulted in a mixed inflammatory cell response, accumulation of peroxidative products, and reduction of GSH content in the skin. Such changes were not observed with MWF treatment alone. These data indicate that oxidative stress can enhance dermal inflammation caused by occupational exposure to MWF.
Influence of 2-bromopropane on reproductive system—Short-term administration of 2-bromopropane inhibits ovulation in F344 rats
Authors: Sekiguchi Soichiro , Asano Goro , Suda Megumi , Honma Takeshi
Published: January 2007

The present study was performed to investigate the toxic effects of 2-bromopropane (2BP) on the female reproductive system. Female F344 rats were administered 2BP (500 or 1000 mg/kg, i.p.) at intervals of 2 or 3 days for 15-17 days. The body weights were measured and estrous stages were observed throughout the experimental period. Ovulation, organ weights, ovarian histology, and blood biochemistry were investigated on the terminal day of the experiment. Uterine weights in rats treated with 2BP were significantly lower than those in control animals. Body, liver, kidney, and adrenal weights in 2BP-treated rats showed no significant differences from control values. 2BP treatment prolonged estrous cycles and decreased the number of ovulated ova in spontaneous ovulation. In addition, histological examinations showed that the preovulatory follicles in the ovary were altered markedly in 2BP groups. These results show that even in short-term treatment, 2BP injured the ovary, particularly the preovulatory follicles. It appears that these damages of the preovulatory follicles induced by 2BP reduced the numbers of spontaneously ovulated ova in female F344 rats.
Genetic polymorphism of metabolic enzymes modifies the risk of chronic solvent-induced encephalopathy
Authors: Kezic Sanja , Calkoen Florentine , Wenker Mira AM , Jacobs John JL , Verberk Maarten M
Published: January 2007

In the present study, we investigate whether genetic polymorphism in enzymes involved in the metabolism of organic solvents influences susceptibility to chronic solvent encephalopathy (CSE), which is one of the major effects of long-term exposure to organic solvents. Polymorphisms in the genes encoding CYP1A1, CYP2E1, EPHX1, GSTM1, GSTT1 and GSTP1 enzymes were determined in a group of male CSE patients ( N = 97) and controls ( N = 214). The selection of the patients was based on a standard diagnostic protocol, including interviews, neuropsychological tests and questionnaires directed to somatic, cognitive and mood symptoms and exposure, in combination with well-defined decision rules. As controls, healthy workers of similar socio-economic background, without memory problems and with no known exposure to organic solvents, were included in the study. Comparing patients and controls, higher frequencies of the variant *5B allele of the CYP2E1 gene (OR: 5.8; 95% CI: 1.8-18.8) and of the variant GSTP1*C allele (OR: 0.40; 95% CI: 0.17-0.94) were found. Homozygous carriers of the exon 4 EPHX1 Arg139 variant allele had a lower risk (OR:0.25; 95% CI: 0.06-1.13).

The present study indicates that genetic polymorphism of CYP2E1, EPHX1 and GSTP1 modify the risk of developing CSE.
Induction and inhibition of pesticide-metabolizing enzymes: roles in synergism of pesticides and pesticide action
Authors: Hodgson Ernest
Published: January 2007

Synergism of the toxic action of pesticides is discussed with particular emphasis on the methylenedioxyphenyl (benzodioxole) (MDP) synergists and on how studies of these compounds may relate to the general significance of pesticide synergism. MDP compounds function as both inhibitors and inducers of cytochrome P450 isoforms, the two processes proceeding, in vivo, at different rates. Inhibition is mediated through the formation of metabolite inhibitory complexes, and induction involves both aryl hydrocarbon (Ah)-dependent and Ah-independent mechanisms. The significance of this biphasic effect on multienzyme xenobiotic metabolizing systems is illustrated by considerations of the insecticide phorate.
Low-dose bioactivity of xenoestrogens in animals: fetal exposure to low doses of methoxychlor and other xenoestrogens increases adult prostate size in mice
Authors: Judy Barbara M. , Nagel Susan C. , Thayer Kristina A. , Saal Frederick S. Vom , Welshons Wade V.
Published: January 2007

The hormonal activity of natural estrogens is influenced by the degree to which they bind to serum proteins. In the pregnant female and in the fetus, greater than 99% of estradiol may be bound by serum binding proteins. Therefore, even though total serum levels of estradiol appear very high in fetuses, we have found that in rodent fetuses, there is a very low free concentration of estradiol (0.2 pg/ml). Naturally occurring variation in fetal serum estradiol predicts differences in numerous postnatal traits, including prostate size. In addition, when this low level of free estradiol was experimentally increased from 0.2 to 0.3 pg/ml during the last third of fetal life, treated male mice showed an increase in adult prostate weight. Fetal exposure to low doses of xenobiotic estrogens by feeding to pregnant females, including the compounds methoxychlor (20 and 2000 μg/kg body weight), DES (0.02 to 2 μg/kg body weight) and bisphenol A (2 and 20 μg/kg body weight), also led to increased prostate weight in adulthood. In contrast, fetal doses of natural estradiol and DES above the physiological range of estrogenic activity, and within a toxicological dose range, led to the opposite outcome, a reduction in subsequent adult prostate weight. This indicates that it may be impossible to assess endocrine-disrupting activities in response to low doses within a physiological range of activity by using high, toxic doses of xenoestrogens in testing procedures. We have developed approaches in vitro to predict the potential estrogenic bioactivity of compounds in the physiologically relevant range in animals and humans. We address the following factors in predicting the final observed endocrine-disrupting effect in the animal: (1) the intrinsic estrogenic activity of a given molecule, (2) the effective free concentration determined by how the molecule is carried in serum, (3) partitioning between aqueous and lipid compartments in body and cell lipids, and (4) absorption and metabolism relative to the route of exposure. The studies and strategies we describe are important in developing criteria for a tiered testing system for the detection of estrogenic chemicals as well as endocrine-disrupting chemicals with different modes of action.
The estrogenic and antiandrogenic pesticide methoxychlor alters the reproductive tract and behavior without affecting pituitary size or LH and prolactin secretion in male rats
Authors: Ostby Joseph , Cooper Ralph L. , Kelce William R. , Gray L. Earl
Published: January 2007

This study was designed to determine if long-term exposure to high doses of methoxychlor (M) would alter pituitary or testicular endocrine functions in either an estrogenic or antiandrogenic manner. Weanling male Long-Evans hooded rats were dosed daily with M (po) at 0, 200, 300, or 400 mg kg−1 day−1 for 10 months. Methoxychlor treatment delayed puberty by as much as 10 weeks and reduced fertility and copulatory plug formation in a dose-related manner at the initial mating. During mating, M-treated males exhibited shorter latencies to mount and ejaculate versus control males, but the number of intromissions prior to ejaculation was unaffected, indicating that M enhanced the arousal level in the males in an estrogen-dependent manner. Most treated males eventually mated but time-to-pregnancy was lengthened. Very low sperm counts were associated with infertility, while prolonged delays in puberty reduced fecundity. Methoxychlor treatment with 200 to 400 mg kg−1 day−1 failed to mimic the chronic effects of a sustained (8 months) low dose of estradiol-17β (3-mm silastic implants) on pituitary or testicular hormone levels. Estradiol administration increased pituitary weight 4-fold, serum levels of luteinizing hormone (LH) were reduced by almost 50%, and serum prolactin was increased 40-fold, while M did not affect any of these measures. These data demonstrate that M affects the CNS, epididymal sperm numbers, and the accessory sex glands and delays mating without significantly affecting the secretion of LH, prolactin, or testosterone. These data indicate that M did not alter pituitary endocrine function in either an estrogenic or antiandrogenic manner. To our knowledge, these data provide the first in vivo example of such a pronounced degree of target tissue selectivity to an environmental endocrine-disrupting chemical.
Environmental antiandrogens: low doses of the fungicide vinclozolin alter sexual differentiation of the male rat
Authors: Ostby Joseph , Monosson Emily , Kelce William R. , Gray L. Earl
Published: January 2007

In humans and rodents, exposure to antiandrogenic chemicals during sexual differentiation can produce malformations of the reproductive tract. Perinatal administration of 100 or 200 mg vinclozolin (V) kg−1 day−1 during sexual differentiation in rats induces female-like anogenital distance (AGD), retained nipples, cleft phallus with hypospadias, suprainguinal ectopic scrota/testes, a vaginal pouch, epididymal granulomas, and small to absent sex accessory glands in male offspring. Vinclozolin is metabolized to at least two active forms, M1 and M2, that display antiandrogenic activity by binding the androgen receptor (AR). Here, we present information on the reproductive effects of oral treatment with low dosage levels of V during sexual differentiation of the male rat. Vinclozolin was administered to the dam at 0, 3.125, 6.25, 12.5, 25, 50, or 100 mg kg−1 day−1 from gestational day 14 to postnatal day 3 (the period of fetal/neonatal testicular testosterone synthesis and sexual differentiation). At doses of 3.125 mg V kg−1 and above, AGD was significantly reduced in newborn male offspring and the incidence of areolas was increased. These effects were associated with permanent alterations in other androgen-dependent tissues. Ventral prostate weight in one year old male offspring was reduced in all treatment groups (significant at 6.25, 25, 50, and 100 mg kg−1 day−1), and permanent nipples were detected in males at 3.125 (1.4%), 6.25 (3.6%), 12.5 (3.9%), 25 (8.5%), 50 (91%), and 100 (100%) mg V kg−1 day−1. To date, permanent nipples have not been observed in a control male from any study in our laboratory. Vinclozolin treatment at 50 and 100 mg kg−1 day−1 induced reproductive tract malformations and reduced ejaculated sperm numbers and fertility. Even though all of the effects of V likely result from the same initial event (AR binding), the different endpoints displayed a wide variety of dose-response curves and ED50's. The dose-response data for several of the functional endpoints failed to display an obvious threshold. These data demonstrate that V produces subtle alterations in sexual differentiation of the external genitalia, ventral prostate, and nipple tissue in male rat offspring at dosage levels below the previously described no-observed-effect-level (NOEL). These effects occur at a dosage level an order of magnitude below that required to induce malformations and reduce fertility. Hence, multigenerational reproduction studies of antiandrogenic chemicals that were not conducted under the Environmental Protection Agency's new Harmonized Multigenerational Test Guidelines, which include endpoints sensitive to antiandrogens at low dosage levels, could yield a NOEL that is at least an order of magnitude too high.
Inadvertent exposure to xenoestrogens in children
Authors: Olea-Serrano Fátima , Lardelli-Claret Pablo , Rivas Ana , Barba-Navarro Alberto , Olea Nicolás
Published: January 2007

This article reviews previous studies and presents new data on pesticide exposure in order to provide some indications of the extent and significance of childhood exposure to xenoestrogens, including pesticides, epoxy resins, and polycarbonates. After more than four decades of pesticide use, little is known about their adverse effects on health. There is a need to address the potential risks associated with the current contamination of water, soils, and foods in many agricultural areas. In southeastern Spain, along the Mediterranean coast, extensive areas alongside residential zones are devoted to intensive farming in plastic greenhouses, with the use of large amounts of pesticides. Human tissue samples have been investigated for pesticide residues. Samples of fat from children living in farm areas contained a total of 14 pesticides, including lindane, HCH, heptachlor, aldrin, dieldrin, endrin, endosulfan, o,p′-DDE, and o,p′-DDD, among others. Of the 113 samples studied, 43 were positive for one or more pesticides, some of which have estrogenic activity. The number of new substances that mimic the action of endogenous estrogens is increasing rapidly. These endocrine-disrupting chemicals are not restricted to pesticides. Several different compounds used in the food industry, in plasticizers, and in dental restorations are also estrogenic. The few studies that have investigated their effects in humans all indicate that concerns are warranted. If there is indeed an association between zexposure to substances with hormone-disruptive activity and certain disorders of sexual maturation, the incidence of such disorders should be greater in areas where exposure to agents with this activity is high. We used a spatial ecological design to search for variations in orchidopexy rates and to analyze relationships between these differences and geographical variations in exposure to pesticides. Our results are compatible with a hypothetical association between exposure to hormone-disruptive chemicals and the induction of cryptorchidism. Several methodological limitations in the study design make it necessary to evaluate the results with caution. In conclusion, a closer scrutiny is required to determine whether epoxy resins and polycarbonates contribute, together with estrogenic pesticides, to the exposure of human consumers, especially children, to xenoestrogens.
Strategies for biological monitoring of exposure for contemporary-use pesticides
Authors: Barr John R. , Driskell W. Jack , Hill Robert H. , Ashley David L. , Needham Larry L. , Head Susan L. , Sampson Eric J. , Barr Dana B.
Published: January 2007

Pesticides are used on a massive scale in the United States. The widespread use of these pesticides has made it virtually impossible for the average person to avoid exposure at some level. Generally, it is believed that low-level exposure to these pesticides does not produce acute toxic effects; however, various cancers and other noncancer health endpoints have been associated with chronic exposure to several groups of pesticides. Therefore, it is imperative that well-designed studies investigate the potential relationship between contemporary pesticide exposure and health effects. For these studies to be accurate, reliable methods for determining individual exposure must be used. Biological monitoring is a useful tool for assessing exposure to some contemporary pesticides. As with any analytical method, biological monitoring entails many difficulties, but, in many instances, they can be overcome by the logical use of available information and information acquired in carefully designed studies. At the Centers for Disease Control and Prevention (CDC), we have acquired extensive experience in the development and application of specific techniques for biological monitoring of a variety of toxicants, including many of the contemporary-use pesticides. We have used these methods to measure the internal dose of pesticides received by people in acute and chronic incidents resulting from both environmental and industrial exposure. Additionally, we have established normative values, or reference ranges, of several pesticides based on measurements of their metabolites in the urine of randomly selected adults in the US population. These data have been successfully used to distinguish overt exposures from `background' exposure. In this paper, we present several examples of the usefulness of biological monitoring in urine and blood and describe the difficulties involved with developing methods in these matrices. We also present a general strategy, considerations, and recommendations for developing biological monitoring techniques for measuring the internal dose of contemporary-use pesticides.
The functional and structural observations of the neonatal reproductive system of alligators exposed in ovo to atrazine, 2,4-D, or estradiol
Authors: Spiteri I. Daniel , Guillette Louis J. , Crain D. Andrew
Published: January 2007

Wild alligators exposed to persistent organochlorine contaminants, municipal waste compounds, and contemporary-use herbicides exhibit reproductive alterations that are thought to be caused by endocrine disruption. This study tests the hypothesis that these alterations, at least in part, result from exposure of alligator embryos to contemporary-use herbicides. Alligator eggs were collected early in development, exposed to estradiol-17β, atrazine, or 2,4-D (at dosages of 0.14, 1.4, and 14 ppm, plus a dosage of 0.014 ppm for estradiol-17β only) before the period of gonadal differentiation, and incubated at a temperature that would produce either 100% males or 100% females. Analysis of histology was performed on the gonads and reproductive tracts of hatchlings. In females, epithelial cell height of the Müllerian duct and medullary regression of the ovary were assessed, whereas in males, sex-cord diameter was measured. Eggs incubated at the female-determining temperature produced all female hatchlings, whereas the estradiol-17β treatments caused the production of females at the male-determining temperature. Neither atrazine nor 2,4-D had this effect. Both Müllerian duct epithelial cell height and medullary regression were increased in estradiol-treated animals, but no differences were noted between herbicide-treated alligators and controls. A previous study found that male alligators exposed to 14 ppm atrazine had elevated gonadal aromatase activity, but there was no difference in sex-cord diameter in this or any other treatment group. Additionally, we observed that hepatic aromatase activity was not altered by in ovo exposure to any of the treatments. These results indicate that these herbicides alone are not responsible for the gonadal abnormalities previously reported for juvenile alligators from Lake Apopka and emphasize the importance of anlyzing both the function ( i.e., steroidogenic enzyme activity) and the structure ( i.e., histological analysis) of the reproductive system. Structural assessment alone may be insufficient for detecting subtle endocrine alterations.
Factors influencing estimation of pesticide-related wildlife mortality
Authors: Vyas Nimish B.
Published: January 2007

Free-ranging wildlife is regularly exposed to pesticides and can serve as a sentinel for human and environmental health. Therefore a comprehensive pesticide hazard assessment must incorporate the effects of actual applications on free-ranging wildlife. Mortality is the most readily reported wildlife effect, and the significance of these data can be realized only when placed in context with the factors that affect the gathering of this type of information. This paper reviews the variables that affect the collection of wildlife mortality data. Data show that most effects on wildlife are not observed, and much of observed mortality is not reported. Delays in reporting or in the response to a report and exposure to multiple stressors distort the exposure-effect relationship and can result in uncertainty in determining the cause of death. The synthesis of information strongly indicates that the actual number of affected animals exceeds the number recovered.
Assessment of risk reduction strategies for the management of agricultural nonpoint source pesticide runoff in estuarine ecosystems
Authors: Fulton Michael H. , Moore David W. , Wirth Edward F. , Chandler G. Thomas , Key Peter B. , Daugomah James W. , Strozier Erich D. , Devane John , Clark James R. , Lewis Michael A. , Finley Dana B. , Ellenberg Walter , Karnaky Karl J. , Scott Geoffrey I.
Published: January 2007

Agricultural nonpoint source (NPS) runoff may result in significant discharges of pesticides, suspended sediments, and fertilizers into estuarine habitats adjacent to agricultural areas or downstream from agricultural watersheds. Exposure of estuarine fin fish and shellfish to toxic levels of pesticides may occur, resulting in significant declines in field populations. Integrated pest management (IPM), best management practices (BMP), and retention ponds (RP) are risk management tools that have been proposed to reduce the contaminant risk from agricultural NPS runoff into estuarine ecosystems. Field studies were conducted at three sites within coastal estuarine ecosystems of South Carolina (SC) from 1985 to 1990 that varied in terms of the amount and degree of risk reduction strategies employed. An intensively managed (IPM, BMP, and RP) agricultural treatment site (TRT) was studied for pesticide runoff impacts. From 1985 to 1987, there were minimal (some IPM and BMP) management activities at TRT, but from 1988 to 1990, TRT was managed using an intensive risk reduction strategy. A second unmanaged agricultural growing area, Kiawah (KWA), was also studied and compared with TRT in terms of pesticide runoff and the resulting impacts on grass shrimp ( Palaemonetes pugio) and mummichogs ( Fundulus heteroclitus). A third, non-agricultural, reference site (CTL) was used for comparing results from the managed and unmanaged agricultural sites. In situ toxicity tests and field samples of the grass shrimp populations were conducted at each site and compared in terms of survival and the effectiveness of current risk reduction strategies. Significant runoff of insecticides (azinphosmethyl, endosulfan, and fenvalerate) along with several fish kills were observed at TRT prior to the implementation of rigorous risk reduction methods. A significant reduction of in stream pesticide concentrations (up to 90%) was observed at TRT following the implementation of strict NPS runoff controls, which greatly reduced impacts on estuarine fish and shellfish. At the unmanaged KWA, continued impacts due to the runoff of these insecticides were observed, along with several fish kills. Additional monitoring indicated that gravid female grass shrimp populations from KWA had elevated levels of P-glycoprotein (P-gp), a multidrug resistance protein, which may transport various pesticides across cellular membranes. Comparison of field results with laboratory toxicity tests established that pesticide exposure was the primary cause of observed field impacts at each site. These findings clearly indicate the value of an integrated risk reduction strategy (BMP, IPM, and RP) for minimizing impacts from NPS agricultural pesticide runoff.