Systematic Review of Potential Health Risks Posed by Pharmaceutical, Occupational and Consumer Exposures to Metallic and Nanoscale Aluminum, Aluminum Oxides, Aluminum Hydroxide and Its Soluble Salts

Aluminum (Al) is a ubiquitous substance encountered both naturally (as the third most abundant element) and intentionally (used in water, foods, pharmaceuticals, and vaccines); it is also present in ambient and occupational airborne particulates. Existing data underscore the importance of Al physical and chemical forms in relation to its uptake, accumulation, and systemic bioavailability. The present review represents a systematic examination of the peer-reviewed literature on the adverse health effects of Al materials published since a previous critical evaluation compiled by Krewski et al. (2007). Challenges encountered in carrying out the present review reflected the experimental use of different physical and chemical Al forms, different routes of administration, and different target organs in relation to the magnitude, frequency, and duration of exposure. Wide variations in diet can result in Al intakes that are often higher than the World Health Organization provisional tolerable weekly intake (PTWI), which is based on studies with Al citrate. Comparing daily dietary Al exposures on the basis of “total Al”assumes that gastrointestinal bioavailability for all dietary Al forms is equivalent to that for Al citrate, an approach that requires validation. Current occupational exposure limits (OELs) for identical Al substances vary as much as 15-fold. The toxicity of different Al forms depends in large measure on their physical behavior and relative solubility in water. The toxicity of soluble Al forms depends upon the delivered dose of Al+ 3 to target tissues. Trivalent Al reacts with water to produce bidentate superoxide coordination spheres [Al(O2)(H2O4)+ 2 and Al(H2O)6 + 3] that after complexation with O2•−, generate Al superoxides [Al(O2•)](H2O5)]+ 2. Semireduced AlO2• radicals deplete mitochondrial Fe and promote generation of H2O2, O2 • − and OH•. Thus, it is the Al+ 3-induced formation of oxygen radicals that accounts for the oxidative damage that leads to intrinsic apoptosis. In contrast, the toxicity of the insoluble Al oxides depends primarily on their behavior as particulates. Aluminum has been held responsible for human morbidity and mortality, but there is no consistent and convincing evidence to associate the Al found in food and drinking water at the doses and chemical forms presently consumed by people living in North America and Western Europe with increased risk for Alzheimer\u27s disease (AD). Neither is there clear evidence to show use of Al-containing underarm antiperspirants or cosmetics increases the risk of AD or breast cancer. Metallic Al, its oxides, and common Al salts have not been shown to be either genotoxic or carcinogenic. Aluminum exposures during neonatal and pediatric parenteral nutrition (PN) can impair bone mineralization and delay neurological development. Adverse effects to vaccines with Al adjuvants have occurred; however, recent controlled trials found that the immunologic response to certain vaccines with Al adjuvants was no greater, and in some cases less than, that after identical vaccination without Al adjuvants. The scientific literature on the adverse health effects of Al is extensive. Health risk assessments for Al must take into account individual co-factors (e.g., age, renal function, diet, gastric pH). Conclusions from the current review point to the need for refinement of the PTWI, reduction of Al contamination in PN solutions, justification for routine addition of Al to vaccines, and harmonization of OELs for Al substances

145. Aluminium and aluminium

Aluminium (Al) is silvery, light, malleable and ductile, and the most abundant metal in the earth’s crust. Al is used primarily for metallurgical purposes, especially to produce Al-based alloy castings and wrought Al. Al compounds are found in consumer products such as antacids, astringents, buffered aspirin, food additives and antiperspirants. Powdered Al metal is often used in explosives and fireworks. No human data were available on respiratory tract and eye irritation following acute/single exposure to Al or Al compounds. Despite the wide use of Al, the small number of reports on effects indicates that Al is not harmful to the skin. Occupational high-level inhalatory exposure to Al can cause lung disorders such as impaired lung function and pulmonary fibrosis. In the most relevant repeated animal inhalation study, rats and guinea pigs were exposed to 0.25, 2.5 or 25 mg/m3 Al chlorohydrate for 6 months. All animals in the two higher dose groups had multifocal granulomatomous pneumonia and microgranulomas in the peribronchial lymph nodes. At the lowest dose, these effects were regarded as minimal. Thus, 0.25 mg/m3 (0.061 mg Al/m3) is probably close to the no-effect level. Some field studies suggest that Al induce subclinical neurotoxic effects, but no exposure-response relationships could be established and co-exposure to other compounds may have played a role. Al compounds are neurotoxic in orally exposed animals at high doses. There are no animal inhalation neurotoxicity studies. Available data indicate that Al is not mutagenic, but that especially the watersoluble sulphate may cause chromosomal damage. Human and experimental animal data do not allow firm conclusions on the potential carcinogenicity of Al or its compounds. Increased cancer mortality rates in workers in the Al production industry especially for lung and urinary bladder is generally considered to be caused by co-exposure to carcinogenic compounds such as polycyclic aromatic hydrocarbons. No studies were found on the effects of occupational exposure to Al or Al compounds on reproductive capacity, pregnancy outcome or postnatal development. In animals, there are studies in which Al compounds were administered in the diet or drinking water. Water-soluble Al compounds have induced postnatal development effects. No effects on prenatal development were reported. Overall, the data are insufficient to identify a critical effect level except for Al chlorohydrate for which minimal pulmonary effects were seen in an animal study at 0.061 mg Al/m3. Keywords: aluminium, fibrosis, lung function, neurotoxicity, occupational exposure limit, pulmonary, review, risk assessment, toxicit

Potential health effects of gasoline and its constituents: current literature (1990-1997) on toxicological data.

We reviewed toxicological studies, both experimental and epidemiological, that appeared in international literature in the period 1990-1997 and included both leaded and unleaded gasolines as well as their components and additives. The aim of this overview was to select, arrange, and present references of scientific papers published during the period under consideration and to summarize the data in order to give a comprehensive picture of the results of toxicological studies performed in laboratory animals (including carcinogenic, teratogenic, or embryotoxic activity), mutagenicity and genotoxic aspects in mammalian and bacterial systems, and epidemiological results obtained in humans in relation to gasoline exposure. This paper draws attention to the inherent difficulties in assessing with precision any potential adverse effects on health, that is, the risk of possible damage to man and his environment from gasoline. The difficulty of risk assessment still exists despite the fact that the studies examined are definitely more technically valid than those of earlier years. The uncertainty in overall risk determination from gasoline exposure also derives from the conflicting results of different studies, from the lack of a correct scientific approach in some studies, from the variable characteristics of the different gasoline mixtures, and from the difficulties of correctly handling potentially confounding variables related to lifestyle (e.g., cigarette smoking, drug use) or to preexisting pathological conditions. In this respect, this paper highlights the need for accurately assessing the conclusive explanations reported in scientific papers so as to avoid the spread of inaccurate or misleading information on gasoline toxicity in nonscientific papers and in mass-media messages

Toxicology of micronutrients: adverse effects and uncertainty

The establishment of safe upper intake levels for micronutrients must consider the intake-response relations for both deficiency and toxicity. Limited data are available on the toxicities of most micronutrients, and few studies that meet the criteria considered essential for the risk assessment of other chemicals in food, such as pesticides and food additives, have been performed. In some cases, the application of large uncertainty factors, which are used to establish the amount of a chemical that would be safe for daily intake throughout life, could result in nutritionally inadequate intakes of micronutrients. As a consequence, lower than normal uncertainty factors have been applied to determine safe or tolerable intakes of many micronutrients. There is no clear scientific rationale, on the basis of the metabolism and elimination of micronutrients or the nature of the adverse effects reported for high intakes, for the use of reduced uncertainty factors for micronutrient toxicity. A review of recent evaluations of selected vitamins and minerals shows little consistency in the application of uncertainty factors by different advisory groups, such as the Institute of Medicine in the United States and the Scientific Committee on Foods in the European Union. It is apparent that, in some cases, the uncertainty factor applied was selected largely to give a result that is compatible with nutritional requirements; therefore, the uncertainty factor represented part of risk management rather than hazard characterization. The usual risk assessment procedures for chemicals in food should be revised for micronutrients, so that the risks associated with intakes that are too low and too high are considered equally as part of a risk-benefit analysis