Deposition of graphene nanomaterial aerosols in human upper airways.

Graphene nanomaterials have attracted wide attention in recent years on their application to state-of-the-art technology due to their outstanding physical properties. On the other hand, the nanotoxicity of graphene materials also has rapidly become a serious concern especially in occupational health. Graphene naomaterials inevitably could become airborne in the workplace during manufacturing processes. The inhalation and subsequent deposition of graphene nanomaterial aerosols in the human respiratory tract could potentially result in adverse health effects to exposed workers. Therefore, investigating the deposition of graphene nanomaterial aerosols in the human airways is an indispensable component of an integral approach to graphene occupational health. For this reason, this study carried out a series of airway replica deposition experiments to obtain original experimental data for graphene aerosol airway deposition. In this study, graphene aerosols were generated, size classified, and delivered into human airway replicas (nasal and oral-to-lung airways). The deposition fraction and deposition efficiency of graphene aerosol in the airway replicas were obtained by a novel experimental approach. The experimental results acquired showed that the fractional deposition of graphene aerosols in airway sections studied were all less than 4%, and the deposition efficiency in each airway section was generally lower than 0.03. These results indicate that the majority of the graphene nanomaterial aerosols inhaled into the human respiratory tract could easily penetrate through the head airways as well as the upper part of the tracheobronchial airways and then transit down to the lower lung airways, where undesired biological responses might be induced.

Deposition of Particles in Human Mouth-Throat Replicas and a USP Induction Port.

BACKGROUND: Oral inhalation is the common route of drug delivery to pulmonary airways. In general, deposition in the oropharyngeal airways from a drug-delivery device makes up a substantial portion of the emitted dose, which affects the dose delivered to the lung. Studies with airway replicas made from cadaver or magnetic resonance imaging scans show that for micrometer-sized particles, impaction is the dominant deposition mechanism. Several deposition studies in oropharyngeal replicas found that the deposition efficiency can be correlated with the mouth inlet velocity and inlet mouthpiece diameter. Other studies show that the deposition efficiency is best correlated with the mean diameter of internal geometry and the mean velocity based on the mean diameter. METHOD: We investigated the mouth inlet diameter, as well as internal airway dimensions and their influence on oropharyngeal deposition based on experimental data from this study. Several human oropharyngeal replicas with different mouth inlet diameters and the USP induction port were used. RESULTS: We found that the aerosol deposition increased with decreasing mouth inlet diameter. Several mathematical expressions were tried to correlate the deposition efficiency with the Stokes number calculated based on (1) mouth inlet diameter and inlet velocity, (2) mean diameter of internal geometry and mean velocity, (3) mouth inlet velocity and mean diameter, and (4) mouth inlet velocity and minimum diameter in the oropharyngeal replica. The best correlation was obtained in case 4. CONCLUSIONS: This correlation could explain the intra-subject variation when deposition was found to vary with mouth inlet diameter, such as in some aerosol drug-delivery devices. It could also explain the intersubject variability in oropharyngeal deposition when human volunteers with different airway geometries and mouth openings were studied.

Carbon nanotubes size classification, characterization and nasal airway deposition.

Workers and researchers in the carbon nanotubes (CNT)-related industries and laboratories might be exposed to CNT aerosols while generating and handling CNT materials. From the viewpoint of occupational health, it is essential to study the deposition of CNT aerosol in the human respiratory tract to investigate the potential adverse health effects. In this study, a human nasal airway replica and two types of CNT materials were employed to conduct CNT nasal airway deposition studies. The two CNT materials were aerosolized by a nebulizer-based wet generation method, with size classified by three designated classification diameters (51, 101 and 215 nm), and then characterized individually in terms of their morphology and aerodynamic diameter. The nasal deposition experiments were carried out by delivering the size classified CNTs into the nasal airway replica in three different inspiratory flow rates. From the characterization study, it showed that the morphology of the size classified CNTs could be in a variety of complex shapes with their physical dimension much larger than their classification diameter. In addition, it was found that the aerodynamic diameters of the classified CNTs were slightly smaller than their classification diameter. The nasal deposition data acquired in this study showed that the deposition efficiency of CNTs in the nasal airway were generally less than 0.1, which implies that the majority of the CNTs inhaled into the nose could easily penetrate through the entire nasal airway and transit further down to the lower airways, possibly causing adverse health effects.

Mechanisms of pharmaceutical aerosol deposition in the respiratory tract.

Aerosol delivery is noninvasive and is effective in much lower doses than required for oral administration. Currently, there are several types of therapeutic aerosol delivery systems, including the pressurized metered-dose inhaler, the dry powder inhaler, the medical nebulizer, the solution mist inhaler, and the nasal sprays. Both oral and nasal inhalation routes are used for the delivery of therapeutic aerosols. Following inhalation therapy, only a fraction of the dose reaches the expected target area. Knowledge of the amount of drug actually deposited is essential in designing the delivery system or devices to optimize the delivery efficiency to the targeted region of the respiratory tract. Aerosol deposition mechanisms in the human respiratory tract have been well studied. Prediction of pharmaceutical aerosol deposition using established lung deposition models has limited success primarily because they underestimated oropharyngeal deposition. Recent studies of oropharyngeal deposition of several drug delivery systems identify other factors associated with the delivery system that dominates the transport and deposition of the oropharyngeal region. Computational fluid dynamic simulation of the aerosol transport and deposition in the respiratory tract has provided important insight into these processes. Investigation of nasal spray deposition mechanisms is also discussed.

Nasal deposition in infants and children.

BACKGROUND: The variability of particle deposition in infant and child nasal airways is significant due to the airway geometry and breathing rate. Estimation of particle deposition in the nasal airway of this age group is necessary, especially for inhalation drug delivery application. Previous studies on nasal aerosol deposition were focused mostly on adult. A few empirical equations were also developed to calculate nasal deposition in different age groups of children. However, those studies have their limitations. The aim of this study is to find a simple way to calculate the nasal aerosol deposition in all age groups. METHODS: An in vitro test of micrometer particle deposition in nasal airways for three different ages of infants and children is conducted. An adult nasal replica is also studied as a comparison. Monodisperse oleic acid aerosols ranging in size between 2 and 28 µm are delivered into the replica at the rest condition. This size range covers the deposition efficiency up to around 100%. This study also compares results from our previous deposition tests with a 5-year-old replica. RESULTS: Nasal deposition of micrometer aerosols in small children and infants is higher than that in adults under equivalent breathing conditions, e.g., sitting awake in this study. Combining the data set of infants, children, and adults, we found the deposition in the nasal airway strongly depends on the particle size and pressure drop. The particle deposition can be calculated based on a single empirical equation in all age groups. The intersubject variability within the same age group was not addressed in this study. CONCLUSIONS: An empirical equation for all age groups is developed. From this equation, particle deposition efficiency in the nasal airway can best be estimated with input data of particle size and pressure drop of the airway.

Evaluation of a novel personal nanoparticle sampler.

This work investigated the performance in terms of collection efficiency and aspiration efficiency of a personal sampler capable of collecting ultrafine particles (nanoparticles) in the occupational environment. This sampler consists of a cyclone for respirable particle classification, micro-orifice impactor stages with an acceleration nozzle to achieve nanoparticle classification and a backup filter to collect nanoparticles. Collection efficiencies of the cyclone and impactor stages were determined using monodisperse polystyrene latex and silver particles, respectively. Calibration of the cyclone and impactor stages showed 50% cut-off diameters of 3.95 µm and 94.7 nm meeting the design requirements. Aspiration efficiencies of the sampler were tested in a wind tunnel with wind speeds of 0.5, 1.0, and 1.5 m s(-1). The test samplers were mounted on a full size mannequin with three orientations toward the wind direction (0°, 90°, and 180°). Monodisperse oleic acid aerosols tagged with sodium fluorescein in the size range of 2 to 10 µm were used in the test. For particles smaller than 2 µm, the fluorescent polystyrene latex particles were generated by using nebulizers. For comparison of the aspiration efficiency, a NIOSH two-stage personal bioaerosol sampler was also tested. Results showed that the orientation-averaged aspiration efficiency for both samplers was close to the inhalable fraction curve. However, the direction of wind strongly affected the aspiration efficiency. The results also showed that the aspiration efficiency was not affected by the ratio of free-stream velocity to the velocity through the sampler orifice. Our evaluation showed that the current design of the personal sampler met the designed criteria for collecting nanoparticles ≤100 nm in occupational environments.

Thoracic fraction of inhaled fiber aerosol.

Size-selective sampling is a health-related method to collect airborne particles based on penetration of inhaled particles into different regions of the human respiratory tract; thus, it is the most relevant sampling method to correlate health risks with occupational exposure. The current practice of sampling asbestos and other fibers is not a size-selective method. The thoracic size fraction, defined as the portion of inhaled particles that can penetrate through the larynx, has been suggested as the most relevant size-selective sampling method for fiber aerosol. The thoracic fraction is based on 1-deposition of inhaled spherical particles in the human extrathoracic airways for mouth breathing and corrected for the particle inhalability. There is no comparable information for fiber aerosols; therefore, there is no technical basis to ascertain whether the current thoracic fraction definition is suitable for fiber aerosols. No human data are available from controlled experiments of inhaled fiber aerosols for the obvious reason that most fiber materials are potentially hazardous when inhaled. Our approach was to measure penetration of fiber aerosol in realistic human oropharyngeal airway replicas and to compare that with data from spherical particles. We showed that realistic human oral airway replicas (including the oral cavity, pharynx, and larynx regions) provided useful spherical and fiber particle deposition in the human head airway. These data could be used to test the thoracic fraction curves. The spherical penetration is in agreement with human in vivo data used to establish the thoracic fraction curve. Fiber penetrations through the larynx of two human oral airway replicas were higher than those for spherical particles for the same aerodynamic diameter using the same replicas. The thoracic curve as defined for spherical particles, therefore, may not include some fibers that could penetrate to the thoracic region.

A wind tunnel test of newly developed personal bioaerosol samplers.

In this study the performance of two newly developed personal bioaerosol samplers was evaluated. The two test samplers are cyclone-based personal samplers that incorporate a recirculating liquid film. The performance evaluations focused on the physical efficiencies that a personal bioaerosol sampler could provide, including aspiration, collection, and capture efficiencies. The evaluation tests were carried out in a wind tunnel, and the test personal samplers were mounted on the chest of a full-size manikin placed in the test chamber of the wind tunnel. Monodisperse fluorescent aerosols ranging from 0.5 to 20 microm were used to challenge the samplers. Two wind speeds of 0.5 and 2.0 m/sec were employed as the test wind speeds in this study. The test results indicated that the aspiration efficiency of the two test samplers closely agreed with the ACGIH inhalable convention within the size range of the test aerosols. The aspiration efficiency was found to be independent of the sampling orientation. The collection efficiency acquired from these two samplers showed that the 50% cutoff diameters were both around 0.6 microm. However the wall loss of these two test samplers increased as the aerosol size increased, and the wall loss of PAS-4 was considerably higher than that of PAS-5, especially in the aerosol size larger than 5 microm, which resulted in PAS-4 having a relatively lower capture efficiency than PAS-5. Overall, the PAS-5 is considered a better personal bioaerosol sampler than the PAS-4.

Determination of in vitro lung solubility and intake-to-dose conversion factor for tritiated lanthanum nickel aluminum alloy.

A sample of tritiated lanthanum nickel aluminum alloy (LaNi4.25Al0.75 or LANA.75) similar to that used at the Savannah River Site Tritium Facilities was analyzed to estimate the particle size distribution of this metal tritide powder and the rate at which this material dissolves in the human respiratory tract after it is inhaled. This information is used to calculate the committed effective dose received by a worker after inhaling the material. These doses, which were calculated using the same methodology given in the U.S. Department of Energy Tritium Handbook, are presented as inhalation intake-to-dose conversion factors (DCF). The DCF for this metal tritide was determined to be 9.4 × 10 Sv Bq, which is less than the DCF for tritiated water. Therefore, the radiation worker bioassay programs designed for tritiated water are adequate to monitor for intakes of this material.

The effect of ventilation, age, and asthmatic condition on ultrafine particle deposition in children.

Ultrafine particles (UFPs) contribute to health risks associated with air pollution, especially respiratory disease in children. Nonetheless, experimental data on UFP deposition in asthmatic children has been minimal. In this study, the effect of ventilation, developing respiratory physiology, and asthmatic condition on the deposition efficiency of ultrafine particles in children was explored. Deposited fractions of UFP (10-200 nm) were determined in 9 asthmatic children, 8 nonasthmatic children, and 5 nonasthmatic adults. Deposition efficiencies in adults served as reference of fully developed respiratory physiologies. A validated deposition model was employed as an auxiliary tool to assess the independent effect of varying ventilation on deposition. Asthmatic conditions were confirmed via pre-and post-bronchodilator spirometry. Subjects were exposed to a hygroscopic aerosol with number geometric mean diameter of 27-31 nm, geometric standard deviation of 1.8-2.0, and concentration of 1.2 × 10(6) particles cm(-3). Exposure was through a silicone mouthpiece. Total deposited fraction (TDF) and normalized deposition rate were 50% and 32% higher in children than in adults. Accounting for tidal volume and age variation, TDF was 21% higher in asthmatic than in non-asthmatic children. The higher health risks of air pollution exposure observed in children and asthmatics might be augmented by their susceptibility to higher dosages of UFP.

Evaluation of physical sampling efficiency for cyclone-based personal bioaerosol samplers in moving air environments.

The need to determine occupational exposure to bioaerosols has notably increased in the past decade, especially for microbiology-related workplaces and laboratories. Recently, two new cyclone-based personal bioaerosol samplers were developed by the National Institute for Occupational Safety and Health (NIOSH) in the USA and the Research Center for Toxicology and Hygienic Regulation of Biopreparations (RCT & HRB) in Russia to monitor bioaerosol exposure in the workplace. Here, a series of wind tunnel experiments were carried out to evaluate the physical sampling performance of these two samplers in moving air conditions, which could provide information for personal biological monitoring in a moving air environment. The experiments were conducted in a small wind tunnel facility using three wind speeds (0.5, 1.0 and 2.0 m s(-1)) and three sampling orientations (0°, 90°, and 180°) with respect to the wind direction. Monodispersed particles ranging from 0.5 to 10 µm were employed as the test aerosols. The evaluation of the physical sampling performance was focused on the aspiration efficiency and capture efficiency of the two samplers. The test results showed that the orientation-averaged aspiration efficiencies of the two samplers closely agreed with the American Conference of Governmental Industrial Hygienists (ACGIH) inhalable convention within the particle sizes used in the evaluation tests, and the effect of the wind speed on the aspiration efficiency was found negligible. The capture efficiencies of these two samplers ranged from 70% to 80%. These data offer important information on the insight into the physical sampling characteristics of the two test samplers.

Exhaled aerosol transmission of pandemic and seasonal H1N1 influenza viruses in the ferret.

Person-to-person transmission of influenza viruses occurs by contact (direct and fomites) and non-contact (droplet and small particle aerosol) routes, but the quantitative dynamics and relative contributions of these routes are incompletely understood. The transmissibility of influenza strains estimated from secondary attack rates in closed human populations is confounded by large variations in population susceptibilities. An experimental method to phenotype strains for transmissibility in an animal model could provide relative efficiencies of transmission. We developed an experimental method to detect exhaled viral aerosol transmission between unanesthetized infected and susceptible ferrets, measured aerosol particle size and number, and quantified the viral genomic RNA in the exhaled aerosol. During brief 3-hour exposures to exhaled viral aerosols in airflow-controlled chambers, three strains of pandemic 2009 H1N1 strains were frequently transmitted to susceptible ferrets. In contrast one seasonal H1N1 strain was not transmitted in spite of higher levels of viral RNA in the exhaled aerosol. Among three pandemic strains, the two strains causing weight loss and illness in the intranasally infected 'donor' ferrets were transmitted less efficiently from the donor than the strain causing no detectable illness, suggesting that the mucosal inflammatory response may attenuate viable exhaled virus. Although exhaled viral RNA remained constant, transmission efficiency diminished from day 1 to day 5 after donor infection. Thus, aerosol transmission between ferrets may be dependent on at least four characteristics of virus-host relationships including the level of exhaled virus, infectious particle size, mucosal inflammation, and viral replication efficiency in susceptible mucosa.

Novel active personal nanoparticle sampler for the exposure assessment of nanoparticles in workplaces.

A novel active personal nanoparticle sampler (PENS), which enables the collection of both respirable particulate mass (RPM) and nanoparticles (NPs) simultaneously, was developed to meet the critical demand for personal sampling of engineered nanomaterials (ENMs) in workplaces. The PENS consists of a respirable cyclone and a micro-orifice impactor with the cutoff aerodynamic diameter (d(pa50)) of 4 µm and 100 nm, respectively. The micro-orifice impactor has a fixed micro-orifice plate (137 nozzles of 55 µm in the inner diameter) and a rotating, silicone oil-coated Teflon filter substrate at 1 rpm to achieve a uniform particle deposition and avoid solid particle bounce. A final filter is used after the impactor to collect the NPs. Calibration results show that the d(pa50) of the respirable cyclone and the micro-orifice impactor are 3.92 ± 0.22 µm and 101.4 ± 0.1 nm, respectively. The d(pa50) at the loaded micro-Al(2)O(3) mass of 0.36-3.18 mg is shifted to 102.9-101.2 nm, respectively, while it is shifted to 98.9-97.8 nm at the loaded nano-TiO(2) mass of 0.92-1.78 mg, respectively. That is, the shift of d(pa50) due to solid particle loading is small if the PENS is not overloaded. Both NPs and RPM concentrations were found to agree well with those of the IOSH respirable cyclone and MOUDI. By using the present PENS, the collected samples can be further analyzed for chemical species concentrations besides gravimetric analysis to determine the actual exposure concentrations of ENMs in both RPM and NPs fractions in workplaces, which are often influenced by the background or incident pollution sources.

Aerosol-assisted synthesis of monodisperse single-crystalline α-cristobalite nanospheres.

Monodisperse single-crystalline α-cristobalite nanospheres have been synthesized by hydrocarbon-pyrolysis-induced carbon deposition on amorphous silica aerosol nanoparticles, devitrification of the coated silica at high temperature, and subsequent carbon removal by oxidation. The nanosphere size can be well controlled by tuning the size of the colloidal silica precursor. Uniform, high-purity nanocrystalline α-cristobalite is important for catalysis, nanocomposites, advanced polishing, and understanding silica nanotoxicology.

Florida Red Tide Toxins (Brevetoxins) and Longitudinal Respiratory Effects in Asthmatics.

Having demonstrated significant and persistent adverse changes in pulmonary function for asthmatics after 1 hour exposure to brevetoxins in Florida red tide (Karenia brevis bloom) aerosols, we assessed the possible longer term health effects in asthmatics from intermittent environmental exposure to brevetoxins over 7 years. 125 asthmatic subjects were assessed for their pulmonary function and reported symptoms before and after 1 hour of environmental exposure to Florida red tide aerosols for upto 11 studies over seven years. As a group, the asthmatics came to the studies with normal standardized percent predicted pulmonary function values. The 38 asthmatics who participated in only one exposure study were more reactive compared to the 36 asthmatics who participated in ≥4 exposure studies. The 36 asthmatics participating in ≥4 exposure studies demonstrated no significant change in their standardized percent predicted pre-exposure pulmonary function over the 7 years of the study. These results indicate that stable asthmatics living in areas with intermittent Florida red tides do not exhibit chronic respiratory effects from intermittent environmental exposure to aerosolized brevetoxins over a 7 year period.

Transmission of aerosolized seasonal H1N1 influenza A to ferrets.

Influenza virus is a major cause of morbidity and mortality worldwide, yet little quantitative understanding of transmission is available to guide evidence-based public health practice. Recent studies of influenza non-contact transmission between ferrets and guinea pigs have provided insights into the relative transmission efficiencies of pandemic and seasonal strains, but the infecting dose and subsequent contagion has not been quantified for most strains. In order to measure the aerosol infectious dose for 50% (aID(50)) of seronegative ferrets, seasonal influenza virus was nebulized into an exposure chamber with controlled airflow limiting inhalation to airborne particles less than 5 µm diameter. Airborne virus was collected by liquid impinger and Teflon filters during nebulization of varying doses of aerosolized virus. Since culturable virus was accurately captured on filters only up to 20 minutes, airborne viral RNA collected during 1-hour exposures was quantified by two assays, a high-throughput RT-PCR/mass spectrometry assay detecting 6 genome segments (Ibis T5000™ Biosensor system) and a standard real time RT-qPCR assay. Using the more sensitive T5000 assay, the aID(50) for A/New Caledonia/20/99 (H1N1) was approximately 4 infectious virus particles under the exposure conditions used. Although seroconversion and sustained levels of viral RNA in upper airway secretions suggested established mucosal infection, viral cultures were almost always negative. Thus after inhalation, this seasonal H1N1 virus may replicate less efficiently than H3N2 virus after mucosal deposition and exhibit less contagion after aerosol exposure.

Comparison of deposition in the USP and physical mouth-throat models with solid and liquid particles.

BACKGROUND: Experimental deposition was studied using three different mouth-throat models: (1) the standard United States Pharmacopeia induction port (IP), (2) the idealized human mouth and throat replica developed by the University of Alberta (UofA replica), and (3) the conductive rubber mouth-throat cast from a human subject developed by Lovelace Respiratory Research Institute (LRRI cast). METHODS: Both solid and liquid monodispersed fluorescent particles in the size range of 2-30 µm in diameter were delivered into the devices at flow rates of 15, 30, and 60 L min(-1). For solid particles, the study was conducted with and without grease coating inside the devices to investigate the effects of particle bounce. CONCLUSIONS: Large amounts of rebounded particles were found for the IP and UofA replica without the coating treatment, while particle bounce was only observed at the large particle size for the LRRI cast. The UofA replica and LRRI cast agreed well for solid particles with coating treatments and liquid particles. The deposition results from this study were also compared to data of in vivo deposition studies from the literature. The deposition efficiencies in the UofA replica and LRRI cast were within the range of in vivo data, which showed a large scatter.

Aerosolized Red Tide Toxins (Brevetoxins) and Asthma: Continued health effects after 1 hour beach exposure.

Blooms of the toxic dinoflagellate, Karenia brevis, produce potent neurotoxins in marine aerosols. Recent studies have demonstrated acute changes in both symptoms and pulmonary function in asthmatics after only 1 hour of beach exposure to these aerosols. This study investigated if there were latent and/or sustained effects in asthmatics in the days following the initial beach exposure during periods with and without an active Florida red tide.Symptom data and spirometry data were collected before and after 1 hour of beach exposure. Subjects kept daily symptom diaries and measured their peak flow each morning for 5 days following beach exposure. During non-exposure periods, there were no significant changes in symptoms or pulmonary function either acutely or over 5 days of follow-up. After the beach exposure during an active Florida red tide, subjects had elevated mean symptoms which did not return to the pre-exposure baseline for at least 4 days. The peak flow measurements decreased after the initial beach exposure, decreased further within 24 hours, and continued to be suppressed even after 5 days. Asthmatics may continue to have increased symptoms and delayed respiratory function suppression for several days after 1 hour of exposure to the Florida red tide toxin aerosols.

Dermal and ocular exposure systems for the development of models of sulfur mustard-induced injury.

Sulfur mustard (SM) is a chemical threat agent for which the effects have no current treatment. Due to the ease of synthesis and dispersal of this material, the need to develop therapeutics is evident. The present article details the techniques used to develop SM laboratory exposure systems for the development of animal models of ocular and dermal injury. These models are critical to enable evaluation of SM injury and therapeutics against that injury. Iterative trials were conducted to optimize dermal and ocular injury models in guinea pigs and rabbits respectively. The goal was a homogeneous and diffuse ocular and dermal injury that compares to the human injury. Dermal exposures were conducted by either a flow-past or static vapor cup system. Ocular exposures were conducted by a static exposure system. Ocular and dermal exposures were conducted with vaporized SM. Vapor concentrations increased with time in the dermal and ocular exposure systems but were stable with varying amounts of applied SM. A dermal deposition estimation study was also conducted. Deposited volumes increased with exposure time.

Review of Florida Red Tide and Human Health Effects.

This paper reviews the literature describing research performed over the past decade on the known and possible exposures and human health effects associated with Florida red tides. These harmful algal blooms are caused by the dinoflagellate, Karenia brevis, and similar organisms, all of which produce a suite of natural toxins known as brevetoxins. Florida red tide research has benefited from a consistently funded, long term research program, that has allowed an interdisciplinary team of researchers to focus their attention on this specific environmental issue-one that is critically important to Gulf of Mexico and other coastal communities. This long-term interdisciplinary approach has allowed the team to engage the local community, identify measures to protect public health, take emerging technologies into the field, forge advances in natural products chemistry, and develop a valuable pharmaceutical product. The Review includes a brief discussion of the Florida red tide organisms and their toxins, and then focuses on the effects of these toxins on animals and humans, including how these effects predict what we might expect to see in exposed people.