For decades, studies of endocrine-disrupting chemicals (EDCs) have challenged traditional concepts in toxicology, in particular the dogma of “the dose makes the poison,” because EDCs can have effects at low doses that are not predicted by effects at higher doses. Here, we review two major concepts in EDC studies: low dose and nonmonotonicity. Low-dose effects were defined by the National Toxicology Program as those that occur in the range of human exposures or effects observed at doses below those used for traditional toxicological studies. We review the mechanistic data for low-dose effects and use a weight-of-evidence approach to analyze five examples from the EDC literature. Additionally, we explore nonmonotonic dose-response curves, defined as a nonlinear relationship between dose and effect where the slope of the curve changes sign somewhere within the range of doses examined. We provide a detailed discussion of the mechanisms responsible for generating these phenomena, plus hundreds of examples from...

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Hormones and endocrine-disrupting chemicals: Low-dose effects and nonmonotonic dose responses

The increasing use of nanomaterials has raised concerns about their potential risks to human health Recent studies have shown that nanoparticles can cross the placenta barrier in pregnant mice and cause neurotoxicity in their offspring, but a more detailed understanding of the effects of nanoparticles on pregnant animals remains elusive Here, we show that silica and titanium dioxide nanoparticles with diameters of 70 nm and 35 nm, respectively, can cause pregnancy complications when injected intravenously into pregnant mice The silica and titanium dioxide nanoparticles were found in the placenta, fetal liver and fetal brain Mice treated with these nanoparticles had smaller uteri and smaller fetuses than untreated controls Fullerene molecules and larger (300 and 1,000 nm) silica particles did not induce these complications These detrimental effects are linked to structural and functional abnormalities in the placenta on the maternal side, and are abolished when the surfaces of the silica nanoparticles are modified with carboxyl and amine groups

Silica and titanium dioxide nanoparticles cause pregnancy complications in mice.

This review summarizes the level of epidemiologic evidence for relationships between prenatal and/or early life exposure to environmental chemical contaminants and fetal, child, and adult health. Discussion focuses on fetal loss, intrauterine growth restriction, preterm birth, birth defects, respiratory and other childhood diseases, neuropsychological deficits, premature or delayed sexual maturation, and certain adult cancers linked to fetal or childhood exposures. Environmental exposures considered here include chemical toxicants in air, water, soil/house dust and foods (including human breast milk), and consumer products. Reports reviewed here included original epidemiologic studies (with at least basic descriptions of methods and results), literature reviews, expert group reports, meta-analyses, and pooled analyses. Levels of evidence for causal relationships were categorized as sufficient, limited, or inadequate according to predefined criteria. There was sufficient epidemiological evidence for causal...

Epidemiologic evidence of relationships between reproductive and child health outcomes and environmental chemical contaminants

Carbonaceous aerosol, a major component of particulate matter (PM), gases, and vapors in the atmosphere, has been associated with natural and anthropogenic air pollution, reduced visibility, climate modulation, material and ecosystem damage, and adverse health effects. More recently, epidemiological studies have indicated associations between organic fractions of ambient PM and adverse respiratory and cardiovascular health outcomes. The effects of the non-PM components of the organic aerosol have received less attention because their measurement in the general environment is not mandated. This article summarizes current knowledge of the nature, prevalence, and health effects of organic aerosols encountered in the outdoor environment, identifies key information gaps, and presents a conceptual framework for research priorities for resolving those gaps. The broad, diverse class of air contaminants comprising organic aerosols may be more important to public health than the modest attention given to them. This review focuses on hazard identification and exposure assessment for evaluating risks to public health from ambient organic aerosols. Current knowledge is insufficient to support a quantitative characterization of the aggregate risk from organic air contaminants. Assessments should be done for individual species or mixtures. Efforts should be taken to assemble and evaluate a common set of standard reference materials for both organic speciation and health response assays. A greater standardization of approaches across studies and laboratories would be useful to achieve uniformity in assessing health effects. Multidisciplinary research efforts are needed to improve the current regulatory-driven air quality monitoring networks for epidemiological studies. The limited array of biomarkers linking organic aerosols to health effects needs to be expanded and specific organic compounds or classes that are associated with biological effects in human cells or animal studies need to be tested for better understanding of the exposure-response relationship.

Health Effects of Organic Aerosols

Continuous exposure to many chemicals, including through air, water, food, or other media and products results in health impacts which have been well assessed, however little is known about the total disease burden related to chemicals. This is important to know for overall policy actions and priorities. In this article the known burden related to selected chemicals or their mixtures, main data gaps, and the link to public health policy are reviewed. A systematic review of the literature for global burden of disease estimates from chemicals was conducted. Global disease due to chemicals was estimated using standard methodology of the Global Burden of Disease. In total, 4.9 million deaths (8.3% of total) and 86 million Disability-Adjusted Life Years (DALYs) (5.7% of total) were attributable to environmental exposure and management of selected chemicals in 2004. The largest contributors include indoor smoke from solid fuel use, outdoor air pollution and second-hand smoke, with 2.0, 1.2 and 0.6 million deaths annually. These are followed by occupational particulates, chemicals involved in acute poisonings, and pesticides involved in self-poisonings, with 375,000, 240,000 and 186,000 annual deaths, respectively. The known burden due to chemicals is considerable. This information supports decision-making in programmes having a role to play in reducing human exposure to toxic chemicals. These figures present only a number of chemicals for which data are available, therefore, they are more likely an underestimate of the actual burden. Chemicals with known health effects, such as dioxins, cadmium, mercury or chronic exposure to pesticides could not be included in this article due to incomplete data and information. Effective public health interventions are known to manage chemicals and limit their public health impacts and should be implemented at national and international levels.

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Knowns and unknowns on burden of disease due to chemicals: a systematic review

The human fetus, child, and adult may experience adverse health outcomes from parental or childhood exposures to environmental toxicants. The fetus and infant are especially vulnerable to toxicants that disrupt developmental processes during relatively narrow time windows. This review summarizes knowledge of associations between child health and development outcomes and environmental exposures, including lead, methylmercury, polychlorinated biphenyls (PCBs), dioxins and related polyhalogenated aromatic hydrocarbons (PHAHs), certain pesticides, environmental tobacco smoke (ETS), aeroallergens, ambient air toxicants (especially particulate matter [PM] and ozone), chlorination disinfection by-products (DBPs), sunlight, power-frequency magnetic fields, radiofrequency (RF) radiation, residential proximity to hazardous waste disposal sites, and solvents. The adverse health effects linked to such exposures include fetal death, birth defects, being small for gestational age (SGA), preterm birth, clinically overt cognitive, neurologic, and behavioral abnormalities, subtle neuropsychologic deficits, childhood cancer, asthma, other respiratory diseases, and acute poisoning. Some environmental toxicants, notably lead, ionizing radiation, ETS, and certain ambient air toxicants, produce adverse health effects at relatively low exposure levels during fetal or child developmental time windows. For the many associations supported by limited or inadequate epidemiologic evidence, major sources of uncertainty include the limited number of studies conducted on specific exposure-outcome relationships and methodologic limitations. The latter include (1) crude exposure indices, (2) limited range of exposure levels, (3) small sample sizes, and (4) limited knowledge and control of potential confounders. Important knowledge gaps include the role of preconceptual paternal exposures, a topic much less studied than maternal or childhood exposures. Large longitudinal studies beginning before or during early pregnancy are urgently needed to accurately measure and assess the relative importance of parental and childhood exposures and evaluate relatively subtle health outcomes such as neuropsychologic and other functional deficits. Large case-control studies are also needed to assess the role of environmental exposures and their interactions with genetic factors in relatively uncommon outcomes such as specific types of birth defects and childhood cancers. There is also an urgent need to accelerate development and use of biomarkers of exposure and genetic susceptibility in epidemiologic studies. This review supports the priority assigned by international agencies to relationships between child health and air quality (indoor and outdoor), lead, pesticides, water contaminants, and ETS. To adequately address such priorities, governments and agencies must strengthen environmental health research capacities and adopt policies to reduce parental and childhood exposures to proven and emerging environmental threats.

Environmental Hazards: Evidence for Effects on Child Health

Abruptio placentae is a serious obstetric condition associated with an increased incidence of perinatal mortality and morbidity. Despite this, there is little information on the occurrence of abruptio placentae in Canada. The Discharge Abstract Database from the Canadian Institute for Health Information was used to identify a cohort of women who had singleton live or stillbirth deliveries in Canada between 1990 and 1997 (n = 2,162,815). Rates of abruptio placentae and abruptio placentae ending in stillbirth were examined by calendar year, province, maternal age and urban/rural status. There is a trend towards an increasing rate of abruptio placentae by year, from 10.9 (95 % confidence interval [CI] 10.5-11.3) cases/1000 deliveries in 1990 to a high of 12.1 (95% CI 11.6-12.5) cases/1000 deliveries in 1996, while the rate ending in stillbirth remained relatively constant. The abruptio placentae rate was highest in mothers over 40 years of age and the case-fatality rate highest in those under 20. These results provide a baseline reference for rates of abruptio placentae in Canada.

Shiliang Liu

Papers

Epidemiologic evidence of relationships between reproductive and child health outcomes and environmental chemical contaminants

Environmental Hazards: Evidence for Effects on Child Health

The occurrence of abruptio placentae in Canada: 1990 to 1997.