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Background: Mixtures of organophosphate and carbamate pesticides are commonly detected in freshwater habitats that support threatened and endangered species of Pacific salmon (Oncorhynchus sp.). These pesticides inhibit the activity of acetylcholinesterase (AChE) and thus have potential to interfere with behaviors that may be essential for salmon survival. Although the effects of individual anticholin-esterase insecticides on aquatic species have been studied for decades, the neurotoxicity of mixtures is still poorly understood.

Objectives: We assessed whether chemicals in a mixture act in isolation (resulting in additive AChE inhibition) or whether components interact to produce either antagonistic or synergistic toxicity.

Methods: We measured brain AChE inhibition in juvenile coho salmon (Oncorhynchus kisutch) exposed to sublethal concentrations of the organophosphates diazinon, malathion, and chlorpyrifos, as well as the carbamates carbaryl and carbofuran. Concentrations of individual chemicals were normalized to their respective median effective concentrations (EC₅₀) and collectively fit to a nonlinear regression. We used this curve to determine whether toxicologic responses to binary mixtures were additive, antagonistic, or synergistic.

Results: We observed addition and synergism, with a greater degree of synergism at higher exposure concentrations. Several combinations of organophosphates were lethal at concentrations that were sublethal in single-chemical trials.

Conclusion: Single-chemical risk assessments are likely to underestimate the impacts of these insecticides on salmon in river systems where mixtures occur. Moreover, mixtures of pesticides that have been commonly reported in salmon habitats may pose a more important challenge for species recovery than previously anticipated.

Background: There is increasing evidence in humans and in experimental animals for a relationship between exposure to specific environmental chemicals and perturbations in levels of critically important thyroid hormones (THs). Identification and proper interpretation of these relationships are required for accurate assessment of risk to public health.

Objectives: We review the role of TH in nervous system development and specific outcomes in adults, the impact of xenobiotics on thyroid signaling, the relationship between adverse outcomes of thyroid disruption and upstream causal biomarkers, and the societal implications of perturbations in thyroid signaling by xenobiotic chemicals.

Data sources: We drew on an extensive body of epidemiologic, toxicologic, and mechanistic studies.

Data synthesis: THs are critical for normal nervous system development, and decreased maternal TH levels are associated with adverse neuropsychological development in children. In adult humans, increased thyroid-stimulating hormone is associated with increased blood pressure and poorer blood lipid profiles, both risk factors for cardiovascular disease and death. These effects of thyroid suppression are observed even within the “normal” range for the population. Environmental chemicals may affect thyroid homeostasis by a number of mechanisms, and multiple chemicals have been identified that interfere with thyroid function by each of the identified mechanisms.

Conclusions: Individuals are potentially vulnerable to adverse effects as a consequence of exposure to thyroid-disrupting chemicals. Any degree of thyroid disruption that affects TH levels on a population basis should be considered a biomarker of adverse outcomes, which may have important societal outcomes.

Background: Cadmium is a widespread environmental pollutant that has been shown to exert toxic effects on kidney and bones in humans after long-term exposure. Urinary cadmium concentration is considered a good biomarker of accumulated cadmium in kidney, and diet is the main source of cadmium among nonsmokers.

Objective: Modeling the link between urinary cadmium and dietary cadmium intake is a key step in the risk assessment of long-term cadmium exposure. There is, however, little knowledge on how this link may vary, especially for susceptible population strata.

Methods: We used a large population-based study (the Swedish Mammography Cohort), with repeated dietary intake data covering a period of 20 years, to compare estimated dietary cadmium intake with urinary cadmium concentrations on an individual basis. A modified version of the Nordberg-Kjellström model and a one-compartment model were evaluated in terms of their predictions of urinary cadmium. We integrated the models and quantified the between-person variability of cadmium half-life in the population. Finally, sensitivity analyses and Monte Carlo simulations were performed to illustrate how the latter model could serve as a robust tool supporting the risk assessment of cadmium in humans.

Results: The one-compartment population model appeared to be an adequate modeling option to link cadmium intake to urinary cadmium and to describe the population variability. We estimated the cadmium half-life to be about 11.6 years, with about 25% population variability.

Conclusions: Population toxicokinetic models can be robust and useful tools for risk assessment of chemicals, because they allow quantification and integration of population variability in toxicokinetics.

Background: The U.S. Environmental Protection Agency is facing large challenges in managing environmental chemicals with increasingly complex requirements for assessing risk that push the limits of our current approaches. To address some of these challenges, the National Research Council (NRC) developed a new vision for toxicity testing. Although the report focused only on toxicity testing, it recognized that exposure science will play a crucial role in a new risk-based framework.

Objective: In this commentary we expand on the important role of exposure science in a fully integrated system for risk assessment. We also elaborate on the exposure research needed to achieve this vision.

Discussion: Exposure science, when applied in an integrated systems approach for risk assessment, can be used to inform and prioritize toxicity testing, describe risks, and verify the outcomes of testing. Exposure research in several areas will be needed to achieve the NRC vision. For example, models are needed to screen chemicals based on exposure. Exposure, dose–response, and biological pathway models must be developed and linked. Advanced computational approaches are required for dose reconstruction. Monitoring methods are needed that easily measure exposure, internal dose, susceptibility, and biological outcome. Finally, population monitoring studies are needed to interpret toxicity test results in terms of real-world risk.

Conclusion: This commentary is a call for the exposure community to step up to the challenge by developing a predictive science with the knowledge and tools for moving into the 21st century.

Background: Diverse environmental contaminants, including the plasticizer di(2-ethylhexyl)phthalate (DEHP), are hepatocarcinogenic peroxisome proliferators in rodents. Peroxisome proliferator–activated receptor-α (PPAR-α) activation and its sequelae have been proposed to constitute a mode of action (MOA) for hepatocarcinogenesis by such agents as a sole causative factor. Further, based on a hypothesized lower sensitivity of humans to this MOA, prior reviews have concluded that rodent hepatocarcinogenesis by PPAR-α agonists is irrelevant to human carcinogenic risk.

Data synthesis: Herein, we review recent studies that experimentally challenge the PPAR-α activation MOA hypothesis, providing evidence that DEHP is hepatocarcinogenic in PPAR-α–null mice and that the MOA but not hepatocarcinogenesis is evoked by PPAR-α activation in a transgenic mouse model. We further examine whether relative potency for PPAR-α activation or other steps in the MOA correlates with tumorigenic potency. In addition, for most PPAR-α agonists of environmental concern, available data are insufficient to characterize relative human sensitivity to this rodent MOA or to induction of hepatocarcinogenesis.

Conclusions: Our review and analyses raise questions about the hypothesized PPAR-α activation MOA as a sole explanation for rodent hepatocarcinogenesis by PPAR-α agonists and therefore its utility as a primary basis for assessing human carcinogenic risk from the diverse compounds that activate PPAR-α. These findings have broad implications for how MOA hypotheses are developed, tested, and applied in human health risk assessment. We discuss alternatives to the current approaches to these key aspects of mechanistic data evaluation.

Background: Hormesis is a binary response phenomenon with low-dose stimulation (or inhibition) of effects by substances producing opposite high-dose responses. Hormesis, after decades of obscurity, has undergone a renaissance in recent years, with rapid growth benefiting greatly from the systematized efforts of such proponents as the hormesis group at the University of Massachusetts-Amherst led by Edward J. Calabrese.

Objective: In this commentary I analyze chemical hormesis methodology with reference to ad hoc scientific approaches for defining and characterizing hormesis.

Discussions: Proponents of hormesis have attempted a scientific characterization of hormesis through a battery of ad hoc methodologies using unvalidated criteria and other mechanisms for persistent database searches rather than through de novo hypothesis testing specific for hormesis. Here I discuss various scientific problems with this search-over-experiment approach, as well as other aspects of attempts at defining and characterizing the field.

Conclusions: Wide acceptance of hormesis by the broad scientific community and adoption of hormesis by public agencies for inclusion in health and regulatory policies have not occurred. Reasons may include the singular nature of hormesis research and directions followed in hormesis methodologies.

Background: A major food safety incident in China was made public in September 2008. Kidney and urinary tract effects, including kidney stones, affected about 300,000 Chinese infants and young children, with six reported deaths. Melamine had been deliberately added at milk-collecting stations to diluted raw milk ostensibly to boost its protein content. Subsequently, melamine has been detected in many milk and milk-containing products, as well as other food and feed products, which were also exported to many countries worldwide.

Objectives: The melamine event represents one of the largest deliberate food contamination incidents. We provide a description and analysis of this event to determine the global implications on food and feed safety.

Discussions: A series of factors, including the intentional character of the milk contamination, the young age of the population affected, the large number of potentially contaminated products, the global distribution of these products, and the delay in reporting led this event to take on unexpected proportions. This incident illustrated the complexity of international trade of food products and food ingredients that required immediate actions at international level.

Conclusion: Managing food-safety events should be done internationally and early on as soon as multinational consequences are expected. Collaboration between food-safety authorities worldwide is needed to efficiently exchange information and to enable tracking and recalling of affected products to ensure food safety and to protect public health.

Background: Several extensive studies of exposure to 2,4-dichlorophenoxyacetic acid (2,4-D) using urinary concentrations in samples from the general population, farm applicators, and farm family members are now available. Reference doses (RfDs) exist for 2,4-D, and Biomonitoring Equivalents (BEs; concentrations in urine or plasma that are consistent with those RfDs) for 2,4-D have recently been derived and published.

Objective: We reviewed the available biomonitoring data for 2,4-D from the United States and Canada and compared them with BE values to draw conclusions regarding the margin of safety for 2,4-D exposures within each population group.

Data sources: Data on urinary 2,4-D excretion in general and target populations from recent published studies are tabulated and the derivation of BE values for 2,4-D summarized.

Data synthesis: The biomonitoring data indicate margins of safety (ratio of BE value to biomarker concentration) of approximately 200 at the central tendency and 50 at the extremes in the general population. Median exposures for applicators and their family members during periods of use appear to be well within acute exposure guidance values.

Conclusions: Biomonitoring data from these studies indicate that current exposures to 2,4-D are below applicable exposure guidance values. This review demonstrates the value of biomonitoring data in assessing population exposures in the context of existing risk assessments using the BE approach. Risk managers can use this approach to integrate the available biomonitoring data into an overall assessment of current risk management practices for 2,4-D.

Objective: In this commentary I respond to points raised in the commentary by Mushak [Ad hoc and fast forward: the science and control of hormesis growth and development. Environ Health Perspect 117:1333–1338 (2009)], which principally concerns studies by me and my colleagues concerning the frequency of hormesis in toxicology.

Discussion: In this commentary I demonstrate that Mushak’s analysis contains critical statistical errors and misunderstandings of statistical concepts that invalidate its conclusions concerning the frequency of hormesis in the toxicologic literature.

Conclusions: In his commentary Mushak offers no significant new conceptual insights, and his key technical criticisms of hormesis frequency findings are unfounded.

Background: Phthalates, ubiquitous environmental pollutants that may disturb the endocrine system, are used primarily as plasticizers of polyvinyl chloride and as additives in consumer and personal care products.

Objectives: In this study, we examined the association between urinary concentrations of nine phthalate metabolites and breast cancer (BC) in Mexican women.

Methods: We age-matched 233 BC cases to 221 women residing in northern Mexico. Sociodemographic and reproductive characteristics were obtained by direct interviews. Phthalates were determined in urine samples (collected pretreatment from the cases) by isotope dilution/high-performance liquid chromatography coupled to tandem mass spectrometry.

Results: Phthalate metabolites were detected in at least 82% of women. The geometric mean concentrations of monoethyl phthalate (MEP) were higher in cases than in controls (169.58 vs. 106.78 μg/g creatinine). Controls showed significantly higher concentrations of mono-n-butyl phthalate, mono(2-ethyl-5-oxohexyl) phthalate, and mono(3-carboxypropyl) phthalate (MCPP) than did the cases. After adjusting for risk factors and other phthalates, MEP urinary concentrations were positively associated with BC [odds ratio (OR), highest vs. lowest tertile = 2.20; 95% confidence interval (CI), 1.33–3.63; p for trend < 0.01]. This association became stronger when estimated for premenopausal women (OR, highest vs. lowest tertile = 4.13; 95% CI, 1.60–10.70; p for trend < 0.01). In contrast, we observed significant negative associations for monobenzyl phthalate (MBzP) and MCPP.

Conclusions: We show for the first time that exposure to diethyl phthalate, the parent compound of MEP, may be associated with increased risk of BC, whereas exposure to the parent phthalates of MBzP and MCPP might be negatively associated. These findings require confirmation.

Background: Biologically based dose–response (BBDR) models can incorporate data on biological processes at the cellular and molecular level to link external exposure to an adverse effect.

Objectives: Our goal was to examine the utility of BBDR models in estimating low-dose risk.

Methods: We reviewed the utility of BBDR models in risk assessment.

Results: BBDR models have been used profitably to evaluate proposed mechanisms of toxicity and identify data gaps. However, these models have not improved the reliability of quantitative predictions of low-dose human risk. In this commentary we identify serious impediments to developing BBDR models for this purpose. BBDR models do not eliminate the need for empirical modeling of the relationship between dose and effect, but only move it from the whole organism to a lower level of biological organization. However, in doing this, BBDR models introduce significant new sources of uncertainty. Quantitative inferences are limited by inter- and intraindividual heterogeneity that cannot be eliminated with available or reasonably anticipated experimental techniques. BBDR modeling does not avoid uncertainties in the mechanisms of toxicity relevant to low-level human exposures. Although implementation of BBDR models for low-dose risk estimation have thus far been limited mainly to cancer modeled using a two-stage clonal expansion framework, these problems are expected to be present in all attempts at BBDR modeling.

Conclusions: The problems discussed here appear so intractable that we conclude that BBDR models are unlikely to be fruitful in reducing uncertainty in quantitative estimates of human risk from low-level exposures in the foreseeable future. Use of in vitro data from recent advances in molecular toxicology in BBDR models is not likely to remove these problems and will introduce new issues regarding extrapolation of data from in vitro systems.

Background: The National Research Council (NRC) Committee on Improving Risk Analysis Approaches Used by the U.S. EPA (Environmental Protection Agency) recommended that low-dose risks be estimated in some situations using human variability distributions (HVDs). HVD modeling estimates log-normal distributions from data on pharmacokinetic and pharmacodynamic variables that affect individual sensitivities to the toxic response. These distributions are combined into an overall log-normal distribution for the threshold dose (dose below which there is no contribution to a toxic response) by assuming the variables act independently and multiplicatively. This distribution is centered at a point-of-departure dose that is usually estimated from animal data. The resulting log-normal distribution is used to quantify low-dose risk.

Objective: We examined the implications of various assumptions in HVD modeling for estimating low-dose risk.

Methods: The assumptions and data used in HVD modeling were subjected to rigorous scrutiny.

Results: We found that the assumption that the variables affecting human sensitivity vary log normally is not scientifically defensible. Other distributions that are equally consistent with the data provide very different estimates of low-dose risk. HVD modeling can also involve an assumption that a threshold dose defined by dichotomizing a continuous apical response has a log-normal distribution. This assumption is shown to be incompatible (except under highly specialized conditions) with assuming that the continuous apical response itself is log normal. However, the two assumptions can lead to very different estimates of low-dose risk. The assumption in HVD modeling that the threshold dose can be expressed as a function of a product of independent variables lacks phenomenological support. We provide an example that shows that this assumption is generally invalid.

Conclusion: In view of these problems, we recommend caution in the use of HVD modeling as a general approach to estimating low-dose risks from human exposures to toxic chemicals.

Background: Hepatocellular carcinoma (HCC), or liver cancer, is the third leading cause of cancer deaths worldwide, with prevalence 16–32 times higher in developing countries than in developed countries. Aflatoxin, a contaminant produced by the fungi Aspergillus flavus and Aspergillus parasiticus in maize and nuts, is a known human liver carcinogen.

Objectives: We sought to determine the global burden of HCC attributable to aflatoxin exposure.

Methods: We conducted a quantitative cancer risk assessment, for which we collected global data on food-borne aflatoxin levels, consumption of aflatoxin-contaminated foods, and hepatitis B virus (HBV) prevalence. We calculated the cancer potency of aflatoxin for HBV-postive and HBV-negative individuals, as well as the uncertainty in all variables, to estimate the global burden of aflatoxin-related HCC.

Results: Of the 550,000–600,000 new HCC cases worldwide each year, about 25,200–155,000 may be attributable to aflatoxin exposure. Most cases occur in sub-Saharan Africa, Southeast Asia, and China where populations suffer from both high HBV prevalence and largely uncontrolled aflatoxin exposure in food.

Conclusions: Aflatoxin may play a causative role in 4.6–28.2% of all global HCC cases.

Background: The presence of pharmaceuticals in aquatic environments and in drinking water has prompted significant public interest regarding potential adverse ecological effects and risks to human health.

Objectives: The Environmental Health Summit held in North Carolina, 10–11 November 2008, explored the issues associated with the presence and relative risk of trace levels of pharmaceuticals in water. More than 150 participants from government organizations and institutions, academia, industry, water utilities, and public interest groups participated in discussions aimed at evaluating the current knowledge on this issue and at identifying research gaps and innovative solution-oriented recommendations.

Discussion: We present different aspects related to the subject that were discussed at the summit, including the source, fate, and transport of pharmaceuticals, their exposure effects and potential risks to human and ecosystems, and the best management practices to address these issues. Recommendations placed emphasis on research needs as well as education, communication, prevention, and intervention programs, and other public health solutions and actions.

Conclusions: Despite rising concerns about the presence of trace amounts of pharmaceuticals in drinking water, little evidence is currently available that associates these chemicals with adverse human health risks. In order to prioritize which pharmaceutical chemicals could potentially pose the highest risk to consumers and the environment, the summit participants concluded that more studies are needed to generate meaningful and accurate data.

Background: Bisphenol A (BPA) is one of the highest-volume chemicals produced worldwide, and human exposure to BPA is thought to be ubiquitous. Thus, there are concerns that the amount of BPA to which humans are exposed may cause adverse health effects. Importantly, results from a large number of biomonitoring studies are at odds with the results from two toxicokinetic studies.

Objective: We examined several possibilities for why biomonitoring and toxicokinetic studies could come to seemingly conflicting conclusions.

Data sources: We examined > 80 published human biomonitoring studies that measured BPA concentrations in human tissues, urine, blood, and other fluids, along with two toxicokinetic studies of human BPA metabolism.

Data extraction and synthesis: The > 80 biomonitoring studies examined included measurements in thousands of individuals from several different countries, and these studies overwhelmingly detected BPA in individual adults, adolescents, and children. Unconjugated BPA was routinely detected in blood (in the nanograms per milliliter range), and conjugated BPA was routinely detected in the vast majority of urine samples (also in the nanograms per milliliter range). In stark contrast, toxicokinetic studies proposed that humans are not internally exposed to BPA. Some regulatory agencies have relied solely on these toxicokinetic models in their risk assessments.

Conclusions: Available data from biomonitoring studies clearly indicate that the general population is exposed to BPA and is at risk from internal exposure to unconjugated BPA. The two toxicokinetic studies that suggested human BPA exposure is negligible have significant deficiencies, are directly contradicted by hypothesis-driven studies, and are therefore not reliable for risk assessment purposes.

Background: Within the past 3 years, four major evaluations of bisphenol A (BPA) safety have been undertaken. However, these assessments have arrived at quite different conclusions regarding the safety of BPA at current human exposure levels.

Objectives: We compared the reasons provided by the European Food Safety Authority (EFSA) BPA risk assessment panel for their conclusion that human exposures are negligible with the conclusions reached by the other panels, with all panels having the same body of literature at their disposal.

Discussion: The EFSA panel dismissed ≥ 80 biomonitoring studies that documented significant levels of BPA exposure in humans, including internal exposures to unconjugated BPA, on the basis that they did not match a model of BPA metabolism. Instead, the EFSA panel relied on two toxicokinetic studies—conducted in 15 adults administered BPA—to draw conclusions about exposure levels in the population, including exposures of neonates.

Conclusions: As with all exposure assessments, models should be developed to explain actual data that are collected. In the case of BPA, samples from a large number of human subjects clearly indicate that humans are internally exposed to unconjugated BPA. The dismissal of these biomonitoring studies simply because their results do not conform to a model violates scientific principles. Expert panels should evaluate all data—including human biomonitoring studies—to make informed risk assessments.

Background: Epidemiologic weight-of-evidence reviews to support regulatory decision making regarding the association between environmental chemical exposures and neurodevelopmental outcomes in children are often complicated by lack of consistency across studies.

Objective: We examined prospective cohort studies evaluating the relation between prenatal and neonatal exposure to polychlorinated biphenyls (PCBs) and neurodevelopment in children to assess the feasibility of conducting a meta-analysis to support decision making.

Data extraction/synthesis: We described studies in terms of exposure and end point categorization, statistical analysis, and reporting of results. We used this evaluation to assess the feasibility of grouping studies into reasonably uniform categories.

Results: The current literature includes 11 cohorts of children for whom effects from prenatal or neonatal PCB exposures were assessed. The most consistently used tests included Brazelton’s Neonatal Behavioral Assessment Scale, the neurologic optimality score in the neonatal period, the Bayley Scales of Infant Development at 5–8 months of age, and the McCarthy Scales of Children’s Abilities in 5-year-olds. Despite administering the same tests at similar ages, the studies were too dissimilar to allow a meaningful quantitative examination of outcomes across cohorts.

Conclusions: These analyses indicate that our ability to conduct weight-of-evidence assessments of the epidemiologic literature on neurotoxicants may be limited, even in the presence of multiple studies, if the available study methods, data analysis, and reporting lack comparability. Our findings add support to previous calls for establishing consensus standards for the conduct, analysis, and reporting of epidemiologic studies in general, and for those evaluating the effects of potential neurotoxic exposures in particular.

Background: Disruption of fundamental biologic processes and associated signaling events may result in clinically significant alterations in lung development.

Objectives: We reviewed evidence on the impact of environmental chemicals on lung development and key signaling events in lung morphogenesis, and the relevance of potential outcomes to public health and regulatory science.

Data sources: We evaluated the peer-reviewed literature on developmental lung biology and toxicology, mechanistic studies, and supporting epidemiology.

Data synthesis: Lung function in infancy predicts pulmonary function throughout life. In utero and early postnatal exposures influence both childhood and adult lung structure and function and may predispose individuals to chronic obstructive lung disease and other disorders. The nutritional and endogenous chemical environment affects development of the lung and can result in altered function in the adult. Studies now suggest that similar adverse impacts may occur in animals and humans after exposure to environmentally relevant doses of certain xenobiotics during critical windows in early life. Potential mechanisms include interference with highly conserved factors in developmental processes such as gene regulation, molecular signaling, and growth factors involved in branching morphogenesis and alveolarization.

Conclusions: Assessment of environmental chemical impacts on the lung requires studies that evaluate specific alterations in structure or function—end points not regularly assessed in standard toxicity tests. Identifying effects on important signaling events may inform protocols of developmental toxicology studies. Such knowledge may enable policies promoting true primary prevention of lung diseases. Evidence of relevant signaling disruption in the absence of adequate developmental toxicology data should influence the size of the uncertainty factors used in risk assessments.

Background: The vision of a National Research Council (NRC) committee (the Committee on Toxicity Testing and Assessment of Environmental Agents) for future toxicity testing involves the testing of human cells in in vitro assays for “toxicity pathways”—normal signaling pathways that when perturbed can lead to adverse effects. Risk assessments would eventually be conducted using mathematical models of toxicity pathways (TP models) to estimate exposures that will not cause biologically significant perturbations in these pathways.

Objectives: In this commentary we present our vision of how risk assessment to support exposure standards will be developed once a suitable suite of in vitro assays becomes available.

Discussion: Issues to be faced basing risk assessments on in vitro data are more complex than, but conceptually similar to, those faced currently when applying in vivo data. Absent some unforeseen technical breakthrough, in vitro data will be used in ways similar to current practices that involve applying uncertainty or safety factors to no observed adverse effect levels or benchmark doses. TP models are unlikely to contribute quantitatively to risk assessments for several reasons, including that the statistical variability inherent in such complex models severely limits their usefulness in estimating small changes in response, and that such models will likely continue to involve empirical modeling of dose responses.

Conclusion: The vision of the committee predicts that chemicals will be tested more quickly and cheaply and that animal testing will be reduced or eliminated. Progress toward achieving these goals will be expedited if the issues raised herein are given careful consideration.

Background: Metal oxide nanoparticles (NPs) have been widely used in industry, cosmetics, and biomedicine.

Objectives: We examined hazards of several well-characterized high production volume NPs because of increasing concern about occupational exposure via inhalation.

Methods: A panel of well-characterized NPs [cerium oxide (CeO₂NP), titanium dioxide (TiO₂NP), carbon black (CBNP), silicon dioxide (SiO₂NP), nickel oxide (NiONP), zinc oxide (ZnONP), copper oxide (CuONP), and amine-modified polystyrene beads] was instilled into lungs of rats. We evaluated the inflammation potencies of these NPs 24 hr and 4 weeks postinstillation. For NPs that caused significant inflammation at 24 hr, we then investigated the characteristics of the inflammation. All exposures were carried out at equal-surface-area doses.

Results: Only CeO₂NP, NiONP, ZnONP, and CuONP were inflammogenic to the lungs of rats at the high doses used. Strikingly, each of these induced a unique inflammatory footprint both acutely (24 hr) and chronically (4 weeks). Acutely, patterns of neutrophil and eosinophil infiltrates differed after CeO₂NP, NiONP, ZnONP, and CuONP treatment. Chronic inflammatory responses also differed after 4 weeks, with neutrophilic, neutrophilic/lymphocytic, eosinophilic/fibrotic/granulomatous, and fibrotic/granulomatous inflammation being caused respectively by CeO₂NP, NiONP, ZnONP, and CuONP.

Conclusion: Different types of inflammation imply different hazards in terms of pathology, risks, and risk severity. In vitro testing could not have differentiated these complex hazard outcomes, and this has important implications for the global strategy for NP hazard assessment. Our results demonstrate that NPs cannot be viewed as a single hazard entity and that risk assessment should be performed separately and with caution for different NPs.