At high concentrations, free radicals and radical-derived, nonradical reactive species are hazardous for living organisms and damage all major cellular constituents. At moderate concentrations, how...

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Free Radicals in the Physiological Control of Cell Function

Although humans have been exposed to airborne nanosized particles (NSPs; < 100 nm) throughout their evolutionary stages, such exposure has increased dramatically over the last century due to anthropogenic sources. The rapidly developing field of nanotechnology is likely to become yet another source through inhalation, ingestion, skin uptake, and injection of engineered nanomaterials. Information about safety and potential hazards is urgently needed. Results of older bio-kinetic studies with NSPs and newer epidemiologic and toxicologic studies with airborne ultrafine particles can be viewed as the basis for the expanding field of nanotoxicology, which can be defined as safety evaluation of engineered nanostructures and nanodevices. Collectively, some emerging concepts of nanotoxicology can be identified from the results of these studies. When inhaled, specific sizes of NSPs are efficiently deposited by diffusional mechanisms in all regions of the respiratory tract. The small size facilitates uptake into cells and transcytosis across epithelial and endothelial cells into the blood and lymph circulation to reach potentially sensitive target sites such as bone marrow, lymph nodes, spleen, and heart. Access to the central nervous system and ganglia via translocation along axons and dendrites of neurons has also been observed. NSPs penetrating the skin distribute via uptake into lymphatic channels. Endocytosis and biokinetics are largely dependent on NSP surface chemistry (coating) and in vivo surface modifications. The greater surface area per mass compared with larger-sized particles of the same chemistry renders NSPs more active biologically. This activity includes a potential for inflammatory and pro-oxidant, but also antioxidant, activity, which can explain early findings showing mixed results in terms of toxicity of NSPs to environmentally relevant species. Evidence of mitochondrial distribution and oxidative stress response after NSP endocytosis points to a need for basic research on their interactions with subcellular structures. Additional considerations for assessing safety of engineered NSPs include careful selections of appropriate and relevant doses/concentrations, the likelihood of increased effects in a compromised organism, and also the benefits of possible desirable effects. An interdisciplinary team approach (e.g., toxicology, materials science, medicine, molecular biology, and bioinformatics, to name a few) is mandatory for nanotoxicology research to arrive at an appropriate risk assessment.

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Nanotoxicology: An Emerging Discipline Evolving from Studies of Ultrafine Particles

The main threats to human health from heavy metals are associated with exposure to lead, cadmium, mercury and arsenic. These metals have been extensively studied and their effects on human health regularly reviewed by international bodies such as the WHO. Heavy metals have been used by humans for thousands of years. Although several adverse health effects of heavy metals have been known for a long time, exposure to heavy metals continues, and is even increasing in some parts of the world, in particular in less developed countries, though emissions have declined in most developed countries over the last 100 years. Cadmium compounds are currently mainly used in re-chargeable nickel-cadmium batteries. Cadmium emissions have increased dramatically during the 20th century, one reason being that cadmium-containing products are rarely re-cycled, but often dumped together with household waste. Cigarette smoking is a major source of cadmium exposure. In non-smokers, food is the most important source of cadmium exposure. Recent data indicate that adverse health effects of cadmium exposure may occur at lower exposure levels than previously anticipated, primarily in the form of kidney damage but possibly also bone effects and fractures. Many individuals in Europe already exceed these exposure levels and the margin is very narrow for large groups. Therefore, measures should be taken to reduce cadmium exposure in the general population in order to minimize the risk of adverse health effects. The general population is primarily exposed to mercury via food, fish being a major source of methyl mercury exposure, and dental amalgam. The general population does not face a significant health risk from methyl mercury, although certain groups with high fish consumption may attain blood levels associated with a low risk of neurological damage to adults. Since there is a risk to the fetus in particular, pregnant women should avoid a high intake of certain fish, such as shark, swordfish and tuna; fish (such as pike, walleye and bass) taken from polluted fresh waters should especially be avoided. There has been a debate on the safety of dental amalgams and claims have been made that mercury from amalgam may cause a variety of diseases. However, there are no studies so far that have been able to show any associations between amalgam fillings and ill health. The general population is exposed to lead from air and food in roughly equal proportions. During the last century, lead emissions to ambient air have caused considerable pollution, mainly due to lead emissions from petrol. Children are particularly susceptible to lead exposure due to high gastrointestinal uptake and the permeable blood-brain barrier. Blood levels in children should be reduced below the levels so far considered acceptable, recent data indicating that there may be neurotoxic effects of lead at lower levels of exposure than previously anticipated. Although lead in petrol has dramatically decreased over the last decades, thereby reducing environmental exposure, phasing out any remaining uses of lead additives in motor fuels should be encouraged. The use of lead-based paints should be abandoned, and lead should not be used in food containers. In particular, the public should be aware of glazed food containers, which may leach lead into food. Exposure to arsenic is mainly via intake of food and drinking water, food being the most important source in most populations. Long-term exposure to arsenic in drinking-water is mainly related to increased risks of skin cancer, but also some other cancers, as well as other skin lesions such as hyperkeratosis and pigmentation changes. Occupational exposure to arsenic, primarily by inhalation, is causally associated with lung cancer. Clear exposure-response relationships and high risks have been observed.

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Hazards of heavy metal contamination.

IN 1974, the International Radiation Protection Association (IRPA) formed a working group on non-ionizing radiation (NIR), which examined the problems arising in the field of protection against the various types of NIR. At the IRPA Congress in Paris in 1977, this working group became the International Non-Ionizing Radiation Committee (INIRC). In cooperation with the Environmental Health Division of the World Health Organization (WHO), the IRPA/INIRC developed a number of health criteria documents on NIR as part of WHO’s Environmental Health Criteria Programme, sponsored by the United Nations Environment Programme (UNEP). Each document includes an overview of the physical characteristics, measurement and instrumentation, sources, and applications of NIR, a thorough review of the literature on biological effects, and an evaluation of the health risks of exposure to NIR. These health criteria have provided the scientific database for the subsequent development of exposure limits and codes of practice relating to NIR. At the Eighth International Congress of the IRPA (Montreal, 18–22 May 1992), a new, independent scientific organization—the International Commission on Non-Ionizing Radiation Protection (ICNIRP)—was established as a successor to the IRPA/INIRC. The functions of the Commission are to investigate the hazards that may be associated with the different forms of NIR, develop international guidelines on NIR exposure limits, and deal with all aspects of NIR protection. Biological effects reported as resulting from exposure to static and extremely-low-frequency (ELF) electric and magnetic fields have been reviewed by UNEP/ WHO/IRPA (1984, 1987). Those publications and a number of others, including UNEP/WHO/IRPA (1993) and Allen et al. (1991), provided the scientific rationale for these guidelines. A glossary of terms appears in the Appendix.

Guidelines for limiting exposure to time-varying electric, magnetic, and electromagnetic fields (up to 300 GHz)

During the last three decades, the impact of chemical pollution has focused almost exclusively on the conventional "priority" pollutants, especially those acutely toxic/carcinogenic pesticides and industrial intermediates displaying persistence in the environment. This spectrum of chemicals, however, is only one piece of the larger puzzle in "holistic" risk assessment. Another diverse group of bioactive chemicals receiving comparatively little attention as potential environmental pollutants includes the pharmaceuticals and active ingredients in personal care products (in this review collectively termed PPCPs), both human and veterinary, including not just prescription drugs and biologics, but also diagnostic agents, "nutraceuticals," fragrances, sun-screen agents, and numerous others. These compounds and their bioactive metabolites can be continually introduced to the aquatic environment as complex mixtures via a number of routes but primarily by both untreated and treated sewage. Aquatic pollution is particularly troublesome because aquatic organisms are captive to continual life-cycle, multigenerational exposure. The possibility for continual but undetectable or unnoticed effects on aquatic organisms is particularly worrisome because effects could accumulate so slowly that major change goes undetected until the cumulative level of these effects finally cascades to irreversible change--change that would otherwise be attributed to natural adaptation or ecologic succession. As opposed to the conventional, persistent priority pollutants, PPCPs need not be persistent if they are continually introduced to surface waters, even at low parts-per-trillion/parts-per-billion concentrations (ng-microg/L). Even though some PPCPs are extremely persistent and introduced to the environment in very high quantities and perhaps have already gained ubiquity worldwide, others could act as if they were persistent, simply because their continual infusion into the aquatic environment serves to sustain perpetual life-cycle exposures for aquatic organisms. This review attempts to synthesize the literature on environmental origin, distribution/occurrence, and effects and to catalyze a more focused discussion in the environmental science community.

Pharmaceuticals and personal care products in the environment: agents of subtle change?

Recent epidemiological studies show an association between particulate air pollution and acute mortality and morbidity down to ambient particle concentrations below 100 micrograms/m3. Whether this association also implies a causality between acute health effects and particle exposure at these low levels is unclear at this time; no mechanism is known that would explain such dramatic effects of low ambient particle concentrations. Based on results of our past and most recent inhalation studies with ultrafine particles in rats, we propose that such particles, that is, particles below approximately 50 nm in diameter, may contribute to the observed increased mortality and morbidity In the past we demonstrated that inhalation of highly insoluble particles of low intrinsic toxicity, such as TiO2, results in significantly increased pulmonary inflammatory responses when their size is in the ultrafine particle range, approximately 20 nm in diameter. However, these effects were not of an acute nature and occurred only after prolonged inhalation exposure of the aggregated ultrafine particles at concentrations in the milligrams per cubic meter range. In contrast, in the course of our most recent studies with thermodegradation products of polytetrafluoroethylene (PTFE) we found that freshly generated PTFE fumes containing singlet ultrafine particles (median diameter 26 nm) were highly toxic to rats at inhaled concentrations of 0.7-1.0 x 10(6) particles/cm3, resulting in acute hemorrhagic pulmonary inflammation and death after 10-30 min of exposure. We also found that work performance of the rats in a running wheel was severely affected by PTFE fume exposure. These results confirm reports from other laboratories of the highly toxic nature of PTFE fumes, which cannot be attributed to gas-phase components of these fumes such as HF, carbonylfluoride, or perfluoroisobutylene, or to reactive radicals. The calculated mass concentration of the inhaled ultrafine PTFE particles in our studies was less than 60 micrograms/m3, a very low value to cause mortality in healthy rats. Aging of the fumes with concomitant aggregation of the ultrafine particles significantly decreases their toxicity. Since ultrafine particles are always present in the urban atmosphere, we suggest that they play a role in causing acute lung injury in sensitive parts of the population.

Association of particulate air pollution and acute mortality: involvement of ultrafine particles?

Enhancement of human performance by caffeine and the amphetamines

Fifteen years ago, in 1991, the U.S. Centers for Disease Control and Prevention (CDC) established 10 mg/dL as the lowest level of concern for children’s blood lead levels. This value is extremely important because, historically, policy makers and public health officials generally have acted to remove sources of lead exposure only after the CDC’s level of concern had been exceeded. A growing body of evidence, however, reveals that blood lead levels below 10 mg/dL may impair neurobehavioral development. There is now sufficient and compelling scientific evidence for the CDC to lower the blood lead action level in children. This review argues that a level of 2 mg/dL is a useful and feasible replacement. Although it can be argued, in turn, that no threshold for the health effects of lead is demonstrable, analytically a blood level of 2 mg/dL is readily and accurately measured and provides a benchmark for successful prevention. Lowering the level of concern would encourage and accelerate the investments needed to ensure that children are protected from lead exposure in their homes, schools, and play settings. Such a program would also offer economic advantages because of the coupling between lead, educational attainment, earnings and anti-social conduct. By lowering the blood action level, CDC will promote policies and initiatives designed to further reduce children’s exposure to this potent developmental neurotoxicant.

A rationale for lowering the blood lead action level from 10 to 2 μg/dL ☆

Mercury is ubiquitous in the global environment, ensuring universal exposure. Some forms of mercury are especially neurotoxic, including clinical signs at high doses. However, typical human exposures occur at low to moderate doses. Only limited data about neurotoxicity at low doses are available, and scientists differ in their interpretation. Dose-response data on neurodevelopment are particularly limited. Despite or perhaps because of the lack of sufficient or consistent scientific data, public concern about a link between mercury exposure and developmental disabilities has been rising. After reviewing the data, the US Environmental Protection Agency proposed a reference dose (an estimate of a daily dose that is likely to be without a risk of adverse effects over a lifetime) for methyl mercury that is substantially lower than previous guidelines from the World Health Organization, the US Agency for Toxic Substances and Disease Registry, and the US Food and Drug Administration. Some questions have been raised about the Environmental Protection Agency's guidelines, but the issue remains unresolved. Meanwhile, consumer groups have raised questions about the potential link between mercury exposure and autism spectrum disorders as well as other adverse neurodevelopmental outcomes. This hypothesis has prompted some parents to seek regulatory, legal, or medical remedies in the absence of firm evidence. This article reviews what is known about mercury neurotoxicity and neurodevelopmental risk. Our intent is to focus the debate about mercury on 1) additional research that should be sought and 2) defining the principal issues that public policy makers face.

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Bernard Weiss

Papers

Association of particulate air pollution and acute mortality: involvement of ultrafine particles?

Enhancement of human performance by caffeine and the amphetamines

A rationale for lowering the blood lead action level from 10 to 2 μg/dL ☆

Mercury Exposure and Child Development Outcomes

Methylmercury developmental neurotoxicity: A comparison of effects in humans and animals