Carcinogenicity of Poorly Soluble Low Toxicity Particles: Commentary on Epidemiology as a Risk Assessment "Reality Check".

Inhaled particles that are poorly soluble or insoluble and of low toxicity ("poorly soluble low toxicity" or "PSLT" particles), can accumulate in the lung and at lung overload levels induce lung cancers in rats. The question of whether PSLT particles increase lung cancer risk in humans is complicated by large differences between rats and humans and the relatively large particle doses administered in animal studies even when compared with heavy human occupational exposures. We review the findings of epidemiological studies on occupational exposure to each of three different PSLT particles (carbon black, talc and taconite). The epidemiological evidence indicates that at even very high occupational exposure levels at which non-malignant respiratory diseases including pneumoconiosis and even talcosis are observed, lung cancer risks appear not to be elevated. Although positive human cancer risks might be predicted based on extrapolation from overload doses in rats to relevant exposures in humans, the epidemiological "reality check" based on the three examples indicates that these PSLT particles are unlikely to increase lung cancer risk in humans even at high occupational levels of exposure. Therefore, we propose that careful evaluation of the epidemiological evidence can serve as a "reality check" for human risk assessment and help balance the risk evaluation process.

In utero arsenic exposure in mice and early life susceptibility to cancer.

In its review of the U.S. Environmental Protection Agency's toxicological review of inorganic arsenic (iAs), the National Academy of Sciences identified carcinogenic endpoints among the highest priority health effects of concern and stated the need to consider evidence that early life exposures may increase the risk of adverse health effects. Recent studies in mice suggest that in utero exposure to arsenic increases susceptibility to cancer later in life. These data are striking in light of the general lack of evidence for carcinogenicity in rodents exposed to iAs. To evaluate the transplacental carcinogenic potential of iAs, a detailed analysis of the toxicology literature evaluating the role of in utero arsenic exposure in carcinogenesis was conducted. Bladder, lung, and skin tumors, which are the tumor types most consistently reported in humans exposed to high arsenic levels, were not consistently increased in mouse studies. There was also a lack of concordance across studies for other tumor types not typically reported in humans. Therefore, we considered methodological and other critical issues that may have contributed to variable results and we suggest additional studies to address these issues. It was concluded that the available data do not provide evidence of a causal link between in utero arsenic exposure and cancer or indicate early life-stage susceptibility to arsenic-induced cancer, particularly at environmentally relevant doses.

Risk assessment of an essential element: manganese.

Manganese (Mn) is an essential element for humans, animals, and plants and is required for growth, development, and maintenance of health. Mn is present in most tissues of all living organisms and is present naturally in rocks, soil, water, and food. High-dose oral, parenteral, or inhalation exposures are associated with increased tissue Mn levels that may lead to development of adverse neurological, reproductive, or respiratory effects. Manganese-induced clinical neurotoxicity is associated with a motor dysfunction syndrome commonly referred to as manganism. Because Mn is an essential element and absorption and excretion are homeostatically regulated, a reasonable hypothesis is that there should be no adverse effects at low exposures. Therefore, there should be a threshold for exposure, below which adverse effects may occur only rarely, if at all, and the frequency of occurrence of adverse effects may increase with higher exposures above that threshold. Lowest-observed-adverse-effect levels (LOAELs), no-observed-adverse-effect levels (NOAELs), and benchmark dose levels (BMDs) have been derived from studies that were conducted to evaluate subclinical neurotoxicity in human occupational cohorts exposed to Mn. Although there is some uncertainty about the predictive value of the subclinical neuromotor or neurobehavioral effects that were observed in these occupational cohort studies, results of the neurological tests were used in risk assessments to establish guidelines and regulations for ambient air levels of Mn in the environment. A discussion of the uncertainties associated with these tests is provided in this review. The application of safety and uncertainty factors result in guidelines for ambient air levels that are lower than the LOAELs, NOAELs, or BMDs from occupational exposure studies by an order of magnitude, or more. Specific early biomarkers of effect, such as subclinical neurobehavioral or neurological changes or magnetic resonance imaging (MRI) changes, have not been established or validated for Mn, although some studies attempted to correlate certain biomarkers with neurological effects. Pharmacokinetic studies with rodents and monkeys provide valuable information about the absorption, bioavailability, and tissue distribution of various Mn compounds with different solubilities and oxidation states in different age groups. These pharmacokinetic studies showed that rodents and primates maintain stable tissue Mn levels as a result of homeostatic mechanisms that tightly regulate absorption and excretion of ingested Mn and limit tissue uptake at low to moderate levels of inhalation exposure. In addition, physiologically based pharmacokinetic (PBPK) models are being developed to provide for the ability to conduct route-to-route extrapolations, evaluate nasal uptake to the central nervous system (CNS), and determine life-stage differences in Mn pharmacokinetics. Such models will facilitate more rigorous quantitative analysis of the available human pharmacokinetic data for Mn and will be used to identify situations that may lead to increased brain accumulation related to altered Mn kinetics in different human populations, and to develop quantitatively accurate predictions of elevated Mn levels that may serve as a basis of dosimetry-based risk assessments. Such dosimetry-based risk assessments will permit for the development of more scientifically refined and robust recommendations, guidelines, and regulations for Mn levels in the ambient environment and occupational settings.

State-of-the-science review: Does manganese exposure during welding pose a neurological risk?

Recent studies report that exposure to manganese (Mn), an essential component of welding electrodes and some steels, results in neurotoxicity and/or Parkinson's disease (PD) in welders. This "state-of-the-science" review presents a critical analysis of the published studies that were conducted on a variety of Mn-exposed occupational cohorts during the last 100 yr, as well as the regulatory history of Mn and welding fumes. Welders often perform a variety of different tasks with varying degrees of duration and ventilation, and hence, to accurately assess Mn exposures that occurred in occupational settings, some specific information on the historical work patterns of welders is desirable. This review includes a discussion of the types of exposures that occur during the welding process--for which limited information relating airborne Mn levels with specific welding activities exists--and the human health studies evaluating neurological effects in welders and other Mn-exposed cohorts, including miners, millers, and battery workers. Findings and implications of studies specifically conducted to evaluate neurobehavioral effects and the prevalence of PD in welders are also discussed. Existing exposure data indicate that, in general, Mn exposures in welders are less than those associated with the reports of clinical neurotoxicity (e.g., "manganism") in miners and smelter workers. It was also found that although manganism was observed in highly exposed workers, the scant exposure-response data available for welders do not support a conclusion that welding is associated with clinical neurotoxicity. The available data might support the development of reasonable "worst-case" exposure estimates for most welding activities, and suggest that exposure simulation studies would significantly refine such estimates. Our review ends with a discussion of the data gaps and areas for future research.

Research strategies for safety evaluation of nanomaterials, part IV: risk assessment of nanoparticles.

Nanoparticles are small-scale substances (<100 nm) with unique properties and, thus, complex exposure and health risk implications. This symposium review summarizes recent findings in exposure and toxicity of nanoparticles and their application for assessing human health risks. Characterization of airborne particles indicates that exposures will depend on particle behavior (e.g., disperse or aggregate) and that accurate, portable, and cost-effective measurement techniques are essential for understanding exposure. Under many conditions, dermal penetration of nanoparticles may be limited for consumer products such as sunscreens, although additional studies are needed on potential photooxidation products, experimental methods, and the effect of skin condition on penetration. Carbon nanotubes apparently have greater pulmonary toxicity (inflammation, granuloma) in mice than fine-scale carbon graphite, and their metal content may affect toxicity. Studies on TiO2 and quartz illustrate the complex relationship between toxicity and particle characteristics, including surface coatings, which make generalizations (e.g., smaller particles are always more toxic) incorrect for some substances. These recent toxicity and exposure data, combined with therapeutic and other related literature, are beginning to shape risk assessments that will be used to regulate the use of nanomaterials in consumer products.

Fate of manganese associated with the inhalation of welding fumes: potential neurological effects.

Welding fumes are a complex mixture composed of different metals. Most welding fumes contain a small percentage of manganese. There is an emerging concern among occupational health officials about the potential neurological effects associated with the exposure to manganese in welding fumes. Little is known about the fate of manganese that is complexed with other metals in the welding particles after inhalation. Depending on the welding process and the composition of the welding electrode, manganese may be present in different oxidation states and have different solubility properties. These differences may affect the biological responses to manganese after the inhalation of welding fumes. Manganese intoxication and the associated neurological symptoms have been reported in individual cases of welders who have been exposed to high concentrations of manganese-containing welding fumes due to work in poorly ventilated areas. However, the question remains as to whether welders who are exposed to low levels of welding fumes over long periods of time are at risk for the development of neurological diseases. For the most part, questions remain unanswered. There is still paucity of adequate scientific reports on welders who suffered significant neurotoxicity, hence there is a need for well-designed epidemiology studies that combine complete information on the occupational exposure of welders with both behavioral and biochemical endpoints of neurotoxicity.

Mutant p53 is constitutively phosphorylated at Serine 15 in UV-induced mouse skin tumors: involvement of ERK1/2 MAP kinase.

Upon DNA damage, phosphorylation and nuclear translocation of wild-type p53 tumor suppressor protein signals its functional activation. However, very little is known about phosphorylation and localization of mutant p53. We found that mutant p53 protein in UV-induced murine primary skin tumors and cultured cell lines was constitutively phosphorylated at serine 15 residue and localized in the cell's nuclei. To investigate the mechanism of constitutive phosphorylation of mutant p53, we tested the involvement of a wide range of protein kinases and found that ERK1/2 mitogen-activated protein kinase was physically associated with mutant p53 in the nucleus. Addition of active recombinant ERK2 kinase protein in vitro to immunoprecipitated mutant p53 resulted in increased phosphorylation at serine 15. Furthermore, ERK1/2 activity was higher in tumor cells than normal cells, suggesting that phosphorylation of mutant p53 at serine 15 depends on the level of ERK1/2 activation. Interestingly, accumulation of mutant p53 in tumor cells was paralleled by low levels of Murine Double Minute 2 protein (MDM2) expression. However, when MDM2 was overexpressed, the fraction of mutant p53 that was phosphorylated at serine 15 resisted degradation, whereas the level of total p53 decreased, suggesting that phosphorylation at serine 15 and downregulation of MDM2 protein may both contribute to stabilization of mutant p53 in tumor cells.