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Journal of Toxicology and Environmental Health, Part B: Special Issue on Endocrine Toxicants and Human Health Risks Volume 11. 2008.
J Toxicol Environ Health B Crit Rev. 2008 Mar;11(3-4):149-51.
Endocrine toxicants with emphasis on human health risks.
Phillips KP, Foster WG.
Faculty of Health Sciences, University of Ottawa, Ottawa, ON, Canada.
Karen.Phillips@uottawa.ca
J Toxicol Environ Health B Crit Rev. 2008 Mar;11(3-4):152-61.
Toward less confusing terminology in endocrine disruptor research.Foster WG, Agzarian J.
Centre for Reproductive Care and Reproductive Biology Division, Department of Obstetrics and Gynecology, McMaster University, Hamilton, Ontario, Canada, L8N 3Z5. fosterw@mcmaster.ca
The realization that environmental contaminants interact with hormone receptors and mimic or antagonize the actions of endogenous hormones led to introduction of terms such as endocrine disruptor, endocrine disrupter, hormonally active chemicals, and hormone mimics into the scientific and lay press. Reports suggesting a link between exposure to chemicals adversely affecting the endocrine system and (1) increasing rates of hormone-dependent cancers (breast, prostate, and testicular), (2) developmental detrimental effects in the male reproductive tract, (3) falling sperm counts, and (4) endometriosis resulted in an explosion of research, regulatory actions, and policy changes aimed at better understanding the hazards posed by these chemicals with subsequent restriction in their use. With increasing concern, there is worldwide action to develop testing strategies to allow for early identification of chemicals possessing endocrine disruptor activity. However, despite an expanding literature and numerous expert panel meetings, there continues to be controversy surrounding how to best define endocrine disruptors, resulting in (1) ambiguous use of the term, (2) confusion in the literature, and (3) publication of contentious lists of chemicals purported to be endocrine disruptors. Herein it is argued in favor of a more restrictive definition with adoption of a less ambiguous term, and in favor of development of a classification system to enhance more effective communication and facilitate appropriate allocation of limited resources in this highly charged area of toxicology.
J Toxicol Environ Health B Crit Rev. 2008 Mar;11(3-4):162-76.
Environmental contaminants and human infertility: hypothesis or cause for concern?
Foster WG, Neal MS, Han MS, Dominguez MM.
Centre for Reproductive Care and Reproductive Biology Division, Department of Obstetrics and Gynecology, McMaster University, Hamilton, Ontario, Canada. fosterw@mcmaster.ca
Throughout the 1980s and 1990s the crude human birth rate (live births per 1000 population) declined, indicating reduced fertility and suggesting a potential decline in fecundity (the potential to conceive). Detection of environmental contaminants in human tissues, together with reports of a global decline in semen quality, further fueled speculation that human infertility rates are increasing and environmental toxicants are potentially important causal agents associated with this change. However, there is little compelling evidence to suggest that infertility rates amongst the general population have changed over time. Moreover, recent studies suggest a rise in the fertility rates. While several studies documented increased time to pregnancy (TTP) in exposed study populations, other investigators were not able to replicate these findings. Nevertheless, studies involving occupational exposure together with results from animal experiments lend support to the conclusion that environmental contaminants potentially adversely affect fertility. Consequently, the impact of exposure to environmental contaminants on human fertility remains controversial. To test the hypothesis that environmental contaminant exposure was associated with enhanced risk of infertility, data concerning trends in fertility and infertility rates were examined to assess the impact of exposure of developing gametes to environmental contaminants. The relationship between exposure and reproductive outcomes was then examined to illustrate the range of adverse effects for reproductive toxicants with data sets of divergent depth and reliability. Data showed that only a weak association between exposure to environmental contaminants and adverse effects on human fertility exists. However, it is postulated that evidence of chemical exposure and potential health consequences of these exposures highlight the need for further research in this area.
J Toxicol Environ Health B Crit Rev. 2008 Mar;11(3-4):177-87.
Endocrine toxicants including 2,3,7,8-terachlorodibenzo-p-dioxin (TCDD) and dioxin-like chemicals and endometriosis: is there a link?Foster WG.
Centre for Reproductive Care, Hamilton Health Sciences, and Reproductive Biology Division, Department of Obstetrics and Gynecology, McMaster University, Hamilton, Ontario, Canada. fosterw@mcmaster.ca
Endometriosis is a common gynecologic disease of unknown etiology affecting approximately 10-15% of women of reproductive age and 50% of infertile women. Estrogen dependence and immune modulation are established features of endometriosis but do not adequately explain the cause of this disorder. In recent years evidence indicated that exposure to environmental toxicants possessing estrogenic activity resulted in endometriosis. However, scant hospital-based case-control studies yielded inconsistent findings and thus did not provide a compelling argument for or against an association between environmental toxicant exposure and endometriosis. Results of animal studies and cell culture experiments, however, suggested that it is biologically plausible for environmental toxicants to affect the pathobiology of endometriosis. In this article, the literature linking environmental toxicants with endometriosis was reviewed and the link with endocrine toxicants discussed.
J Toxicol Environ Health B Crit Rev. 2008 Mar;11(3-4):188-220.
Human exposure to endocrine disrupters and semen quality.
Phillips KP, Tanphaichitr N.
Faculty of Health Sciences, University of Ottawa, Ottawa, Ontario, Canada. Karen.Phillips@uottawa.ca
Reproductive pathology in the male represents about 20% of infertility cases. Male infertility may be attributed to a number of causes, including genetic and congenital abnormalities, infection, multisystemic diseases, varicocele, and others; however, a significant number of cases are idiopathic. Global declines in semen quality were suggested to be associated with enhanced exposure to environmental chemicals that act as endocrine disrupters as a result of our increased use of pesticides, plastics, and other anthropogenic materials. A significant body of toxicology data based upon laboratory and wildlife animals studies suggests that exposure to certain endocrine disrupters is associated with reproductive toxicity, including (1) abnormalities of the male reproductive tract (cryptorchidism, hypospadias), (2) reduced semen quality, and (3) impaired fertility in the adult. There is, however, a relative paucity of studies designed to measure exposure to endocrine disrupters on semen quality parameters (sperm concentration, motility, morphology). An overview of the human semen quality literature is presented that examines the role of endocrine disrupters including organochlorines (OC), dioxins, phthalates, phytoestrogens, and chemical mixtures (pesticides and tobacco smoke).
J Toxicol Environ Health B Crit Rev. 2008 Mar;11(3-4):221-41.
The influence of the environment and other exogenous agents on spontaneous abortion risk.
Weselak M, Arbuckle TE, Walker MC, Krewski D.
McLaughlin Centre for Population Health Risk Assessment, Institute of Population Health, University of Ottawa, Ottawa, Ontario, Canada. mandy_weselak@hc-sc.gc.ca
It is estimated that close to 30% of all pregnancies end in spontaneous abortion. Although about 60% of spontaneous abortions are thought to be due to genetic, infectious, hormonal, and immunological factors, the role of the environment remains poorly understood. Pregnancy involves a delicate balance of hormonal and immunological functions, which may be affected by environmental substances. Many toxic substances that are persistent in the environment and accumulate in the fatty tissues may disrupt this equilibrium. This overview addresses known risk factors for spontaneous abortions and examines the role, if any, that environmental factors (chemical and physical) may play in the etiology of this adverse health outcome.
J Toxicol Environ Health B Crit Rev. 2008 Mar;11(3-4):242-59.
Role of hormonal and other factors in human prostate cancer.
Wigle DT, Turner MC, Gomes J, Parent ME.
McLaughlin Centre for Population Health Risk Assessment, Institute of Population Health, University of Ottawa, Ottawa, Ontario, Canada. don.wigle@sympatico.ca
American men have a lifetime risk of about 18% for prostate cancer diagnosis. Large international variations in prostate cancer risks and increased risks among migrants from low- to high-risk countries indicate important roles for environmental factors. Major known risk factors include age, family history, and country/ethnicity. Type 2 diabetes appears to reduce risk, while high birth weight and adult height are linked to increased risk of aggressive prostate cancer. Limited evidence supports an association with a history of sexually transmitted infections. A previous meta-analysis of eight cohort studies indicated no associations with plasma androgen, estrogen, or sex hormone binding globulin (SHBG) levels. However, there were dose-response relationships with baseline plasma testosterone levels in two studies that adjusted for other serum hormones and obesity. Finasteride (a drug that blocks testosterone activation) reduced prostate cancer risk by 25%. Low-frequency genes linked to familial prostate cancer only explain a small fraction of all cases. Sporadic cases were linked to relatively common polymorphisms of genes involved in (1) androgen synthesis, activation, inactivation and excretion, (2) hormone and vitamin D receptors, (3) carcinogen metabolism, and (4) DNA repair. Epidemiologic evidence supports protective roles for dietary selenium, vitamin E, pulses, tomatoes/lycopene, and soy foods, and high plasma 1,25-dihydroxyvitamin D levels. There is inadequate evidence that vegetables, fruit, carotenoids, and vitamins A and C reduce risk and that animal fat, alpha-linoleic acid, meat, coffee, and tea increase risk. Two major cohort studies found dose-response relationships with dietary calcium intake. Total dietary energy intake may enhance risk. Limited evidence supports a protective role for physical activity and elevated risk for farmers and other men with occupational pesticide exposure, particularly to organochlorine compounds and phenoxy herbicides. There is inadequate evidence for a relationship with alcohol or smoking. Most known or suspected external risk factors may act through hormonal mechanisms, but our review found little supporting evidence, and substantial further research is needed.
J Toxicol Environ Health B Crit Rev. 2008 Mar;11(3-4):260-75.
Testicular cancer and hormonally active agents.Garner M, Turner MC, Ghadirian P, Krewski D, Wade M.
McLaughlin Center for Population Health Risk Assessment, University of Ottawa, Ottawa, Ontario, Canada.
Testicular cancer (TC) is a rare form of cancer, accounting for 1% of all new cancer cases in Canadian males. TC is the most common malignancy among young men, aged 25-34 yr old. Over previous decades, the incidence of TC has increased in many Western countries. Countries with a sufficiently long period of cancer registration, such as Denmark, document this trend back to the first half of the 20th century. The etiology of TC remains poorly understood. Most of the established risk factors are likely related to in utero events, including some factors that are purported to be surrogate measures for exposure to endogenous estrogens. The correlation of TC with other testicular abnormalities and with pregnancy factors led to the proposal that these conditions are a constellation of sequelae of impairment of testicular development called testis dysgenesis syndrome. There is some limited evidence suggesting that exposure to pharmacological estrogens may contribute to some cases of TC. There is currently no compelling evidence that exposure to environmental estrogenic or other hormonally active substances is contributing to the rise in TC incidence observed in Western nations over the last several decades; however, this question has not been extensively studied. The (1) rarity of this condition in the population, (2) long lag time between the presumed sensitive period during fetal development and clinical appearance of the condition, and (3) lack of a good animal model to study the progression of the disease have greatly hindered the understanding of environmental influences on TC risk.
J Toxicol Environ Health B Crit Rev. 2008 Mar;11(3-4):276-300.
Review of the etiology of breast cancer with special attention to organochlorines as potential endocrine disruptors.
Salehi F, Turner MC, Phillips KP, Wigle DT, Krewski D, Aronson KJ.
McLaughlin Centre for Population Health Risk Assessment, Institute of Population Health, University of Ottawa, Ottawa, Canada.
Breast cancer is the most frequently diagnosed cancer among Canadian women, accounting for about 30% of all new cancer cases each year. Although the incidence of breast cancer has increased over the past 50 years, the cause of this rise is unknown. Risk factors for breast cancer may be classified into four broad categories: (1) genetic/familial, (2) reproductive/hormonal, (3) lifestyle, and (4) environmental. Established risk factors for breast cancer include older age, later age at first full-term pregnancy, no full-term pregnancies, postmenopausal obesity, and genetic factors. However, these known risk factors cannot account for the majority of cases. In the early 1990s, it was suggested that exposure to some environmental chemicals such as organochlorine compounds may play a causal role in the etiology of breast cancer through estrogen-related pathways. The relationship between organochlorines and breast cancer risk has been studied extensively in the past decade and more, and at this point there is no clear evidence to support a causal role of most organochlorine pesticides in the etiology of human breast cancer, but more evidence is needed to assess risk associated with polychlorinated biphenyls (PCBs). Future studies need to consider the combined effects of exposures, concentrate on vulnerable groups such as those with higher levels of exposure, only consider exposures occurring during the most etiologically relevant time periods, and more thoroughly consider gene-environment interactions.
J Toxicol Environ Health B Crit Rev. 2008 Mar;11(3-4):301-21.
Risk factors for ovarian cancer: an overview with emphasis on hormonal factors.Salehi F, Dunfield L, Phillips KP, Krewski D, Vanderhyden BC.
McLaughlin Center for Population Health Risk Assessment, University of Ottawa, Ottawa, Ontario, Canada.
Ovarian cancer is the fifth most frequently occurring cancer among women and leading cause of gynecological cancer deaths in North America. Although the etiology of ovarian cancer is not clear, certain factors are implicated in the etiology of this disease, such as ovulation, gonadotropic and steroid hormones, germ cell depletion, oncogenes and tumor suppressor genes, growth factors, cytokines, and environmental agents. Family history of breast or ovarian cancer is a prominent risk factor for ovarian cancer, with 5-10% of ovarian cancers due to heritable risk. Reproductive factors such as age at menopause and infertility contribute to greater risk of ovarian cancer, whereas pregnancy, tubal ligation, and hysterectomy reduce risk. Oral contraceptive (OC) use has clearly been shown to be protective against ovarian cancer. In contrast, large epidemiologic studies found hormone replacement therapy (HRT) to be a greater risk factor for ovarian cancer. The marked influence of hormones and reproductive factors on ovarian cancer suggests that endocrine disrupters may impact risk; however, there is a notable lack of research in this area. Lifestyle factors such as cigarette smoking, obesity, and diet may affect ovarian cancer risk. Exposure to certain environmental agents such as talc, pesticides, and herbicides may increase risk of ovarian cancer; however, these studies are limited. Further research is needed to strengthen the database of information from which an assessment of environmental and toxicological risk factors for ovarian cancer can be made.\
J Toxicol Environ Health B Crit Rev. 2008 Mar;11(3-4):322-44.
Key developments in endocrine disrupter research and human health.
Phillips KP, Foster WG.
Faculty of Health Sciences, University of Ottawa, Ottawa, ON, Canada. Karen.Phillips@uottawa.ca
Environmental etiologies involving exposures to chemicals that mimic endogenous hormones are proposed for a number of adverse human health effects, including infertility, abnormal prenatal and childhood development, and reproductive cancers (National Research Council, 1999; World Health Organization, 2002). Endocrine disrupters represent a significant area of environmental research with important implications for human health. This article provides an overview of some of the key developments in this field that may enhance our ability to assess the human health risks posed by exposure to endocrine disrupters. Advances in methodologies of hazard identification (toxicogenomics, transcriptomics, proteomics, metabolomics, bioinformatics) are discussed, as well as epigenetics and emerging biological endpoints.
J Toxicol Environ Health B Crit Rev. 2008 Mar;11(3-4):345-50.
Risk communication of endocrine-disrupting chemicals: improving knowledge translation and transfer.
Tyshenko MG, Phillips KP, Mehta M, Poirier R, Leiss W.
McLaughlin Centre for Population Health Risk Assessment, Institute of Population Health, University of Ottawa, Ottawa, Ontario, Canada. mtyshenk@uottawa.ca
Public perception of the negative effects of endocrine-disrupting chemicals appears to be higher compared to other chemical pollutants, due to (1) chronic, low-probability effects, and (2) uncertainties about which biological effects may be relevant for human health. Individuals, both expert and lay public, require credible, trustworthy, and understandable information about the scientific evidence of endocrine-disrupting chemicals in order to make informed risk decisions. The creation of a dedicated web site, http://www.emcom.ca, as a tool for knowledge translation and transfer provides the general public with access to scientific experts and bridges the gap between experts and nonexperts through a two-way, interactive communications approach. By obtaining accurate and credible information, individuals can make better-informed decisions concerning endocrine-disrupting chemicals.
J Toxicol Environ Health B Crit Rev. 2008 Mar;11(3-4):351-72.
Assessing and managing risks arising from exposure to endocrine-active chemicals.
Phillips KP, Foster WG, Leiss W, Sahni V, Karyakina N, Turner MC, Kacew S, Krewski D.
Faculty of Health Sciences, University of Ottawa, Ontario, Canada. Karen.Phillips@uottawa.ca
Managing risks to human health and the environment produced by endocrine-active chemicals (EAC) is dependent on sound principles of risk assessment and risk management, which need to be adapted to address the uncertainties in the state of the science of EAC. Quantifying EAC hazard identification, mechanisms of action, and dose-response curves is complicated by a range of chemical structure/toxicology classes, receptors and receptor subtypes, and nonlinear dose-response curves with low-dose effects. Advances in risk science including toxicogenomics and quantitative structure-activity relationships (QSAR) along with a return to the biological process of hormesis are proposed to complement existing risk assessment strategies, including that of the Endocrine Disruptor Screening and Testing Advisory Committee (EDSTAC 1998). EAC represents a policy issue that has captured the public's fears and concerns about environmental health. This overview describes the process of EAC risk assessment and risk management in the context of traditional risk management frameworks, with emphasis on the National Research Council Framework (1983), taking into consideration the strategies for EAC management in Canada, the United States, and the European Union.
