Bioaccessibility of Metallic Nickel and Nickel Oxide Nanoparticles in Four Simulated Biological Fluids.

Bioaccessibility of metals from substances and alloys is increasingly used as part of the assessment to predict potential toxicity. However, data are sparse on the metal bioaccessibility from nanoparticle (NP) size metal substances. This study examines nickel ion release from metallic nickel and nickel oxide micron particles (MPs) and NPs in simulated biological fluids at various timepoints including those relevant for specific routes of exposure. The results suggest that MPs of both metallic nickel and nickel oxide generally released more nickel ions in acidic simulated biological fluids (gastric and lysosomal) than NPs of the same substance, with the largest differences being for nickel oxide. In more neutral pH fluids (interstitial and perspiration), nickel metal NPs released more nickel ions than MPs, with nickel oxide results showing a higher release for MPs in interstitial fluid yet a lower release in perspiration fluid. Various experimental factors related to the particle, fluid, and extraction duration were identified that can have an impact on the particle dissolution and release of nickel ions. Overall, the results suggest that based on nickel release alone, nickel NPs are not inherently more hazardous than nickel MPs. Moreover, analyses should be performed on a case-by-case basis with consideration of various experimental factors and correlation with in vivo data.

An Assessment of the Oral and Inhalation Acute Toxicity of Nickel Oxide Nanoparticles in Rats.

Nickel oxide nanoparticles (NiO NPs) have been the focus of many toxicity studies. However, acute toxicity studies that identify toxicological dose descriptors, such as an LC50 or LD50, are lacking. In this paper, the acute toxicity of NiO NPs was evaluated in albino-derived Sprague-Dawley rats through OECD guideline studies conducted by both the oral and inhalation routes of exposure. The animals were assessed for mortality, body weight, behavioral observations, and gross necropsy. Results from previously conducted (unpublished) acute inhalation studies with larger NiO microparticles (MPs) are also included for comparison. Mortality, the primary endpoint in acute toxicity studies, was not observed for rats exposed to NiO NPs via either the oral or inhalation exposure routes, with a determined LD50 of >5000 mg/kg and an LC50 > 5.42 mg/L, respectively. Our results suggest that these NiO NPs do not exhibit serious acute toxicity in rats or warrant an acute toxicity classification under the current GHS classification criteria. This aligns with similar results for NiO MPs from this and previously published studies.

Comparative pulmonary and genotoxic responses to inhaled nickel subsulfide and nickel sulfate in F344 rats.

Inhalation studies with nickel (Ni) subsulfide (Ni3 S2 ) and Ni sulfate hexahydrate (NiSO4 ·6H2 O) investigated differences in mode of action that could explain why the former induced lung tumors in rats and the latter did not. Male rats were exposed to ≤0.22 mg Ni/m3 NiSO4 ·6H2 O or 0.44 mg Ni/m3 Ni3 S2 , 6 h/day, 5 days/week for 3 and 13 weeks; subsets of the rats exposed for 13 weeks were held for an additional 13 weeks. Analyses of bronchoalveolar lavage fluid, isolated cells, and whole lung tissue were conducted to compare the extent and persistence of any induced lung effects. Histological findings were qualitatively identical for both compounds and consistent with lesions reported in earlier studies. After 13 weeks of exposure, the incidence and severity of pulmonary inflammation and epithelial cell hyperplasia were greater among Ni3 S2 -exposed rats, whereas the reverse response was seen for apoptosis. Only Ni3 S2 exposure significantly increased epithelial and non-epithelial cell proliferation after 13 weeks of exposure. Both compounds induced DNA damage in isolated lung cells and DNA hypermethylation of whole lung tissue after 13 weeks of exposure at the highest exposure concentrations. Increases in cell proliferation, DNA damage, and tissue DNA hypermethylation did not persist during the 13-week recovery period. In summary, the highest concentrations of each compound produced marked pulmonary toxicity, but the lowest concentrations produced minimal or no effects. Differences in the proliferative and apoptotic responses between the two compounds may help explain differences in carcinogenicity, whereas the identification of no observed adverse effect concentrations (NOAECs) contributes to the risk characterization for inhalation exposure to nickel compounds.

Bioaccessibility of nickel and cobalt in synthetic gastric and lung fluids and its potential use in alloy classification.

This study investigated nickel and cobalt ion release from the metals and several alloys in synthetic gastric, as well as interstitial and lysosomal lung fluids. Results were used to calculate the relative bioaccessible concentrations (RBCs) of the metals. Nickel release from SS 316L powder in gastric fluid was >300-fold lower than from a simple mixture of powders of the same bulk composition. Gastric bioaccessibility data showed 50-fold higher metal releases per gram of sample from powder than massive forms. RBCs of nickel and cobalt in the alloy powders were lower, equal, or higher in all fluids tested than their bulk concentrations. This illustrates the fact that matrix effects can increase or decrease the metal ion release, depending on the metal ingredients, alloy type, and fluid, consistent with research by others. Acute inhalation toxicity studies with cobalt-containing alloy powders showed that the RBC of cobalt in interstitial lung fluid predicted acute toxicity better than bulk concentration. This example indicates that the RBC of a metal in an alloy may estimate the concentration of bioavailable metals better than the bulk concentration, and the approach may provide a means to refine the classification of alloys for several human health endpoints.

Derivation of an oral toxicity reference value for nickel.

Nickel (Ni) is in the earth's crust and can be found in environmental compartments such as water, soil, and air, as well as food. This paper presents an assessment of the oral nickel toxicity data in support of non-cancer health-based oral exposure limits or toxicity reference values (TRVs). This paper derives TRVs for three populations of interest: adults, toddlers, and people who have been dermally sensitized to nickel. The adult/lifetime TRV of 20 µg Ni/kg-day is based on post-implantation loss/perinatal mortality in a 2-generation reproductive study in rats. Several recent assessments by regulatory agencies have used the same study and endpoint, but the dose-response modeling conducted here was more appropriate for the study design. Toxicokinetic data from rats and humans indicate that the applied uncertainty factors are very conservative. Because the endpoint relates to fetal exposure and is not relevant to toddlers, a toddler TRV was derived based on decreased body weight in young rats; this TRV was also 20 µg Ni/kg-day. A separate TRV of 4 µg Ni/kg in addition to Ni in food was derived for protection of nickel-sensitized populations from flare-up of dermatitis, based on studies of single exposures in humans under conditions that maximize oral absorption.

Incorporation of dosimetry in the derivation of reference concentrations for ambient or workplace air: a conceptual approach.

Dosimetric models are essential tools to refine inhalation risk assessments based on local respiratory effects. Dosimetric adjustments to account for differences in aerosol particle size and respiratory tract deposition and/or clearance among rodents, workers, and the general public can be applied to experimentally- and epidemiologically-determined points of departure (PODs) to calculate size-selected (e.g., PM10, inhalable aerosol fraction, respirable aerosol fraction) equivalent concentrations (e.g., HEC or Human Equivalent Concentration; REC or Rodent Equivalent Concentration). A modified POD (e.g., HEC) can then feed into existing frameworks for the derivation of occupational or ambient air concentration limits or reference concentrations. HECs that are expressed in terms of aerosol particle sizes experienced by humans but are derived from animal studies allow proper comparison of exposure levels and associated health effects in animals and humans. This can inform differences in responsiveness between animals and humans, based on the same deposited or retained doses and can also allow the use of both data sources in an integrated weight of evidence approach for hazard and risk assessment purposes. Whenever possible, default values should be replaced by substance-specific and target population-specific parameters. Assumptions and sources of uncertainty need to be clearly reported.

Assessment of human exposure to environmental sources of nickel in Europe: Inhalation exposure.

The paper describes the inhalation nickel (Ni) exposure of humans via the environment for the regional scale in the EU, together with a tiered approach for assessing additional local exposure from industrial emissions. The approach was designed, in the context of REACH, for the purpose of assessing and controlling emissions and air quality in the neighbourhood of Ni producers and downstream users. Two Derived No Effect Level (DNEL) values for chronic inhalation exposure to total Ni in PM10 (20 and 60ngNi/m(3)) were considered. The value of 20ngNi/m(3) is the current EU air quality guidance value. The value of 60ngNi/m(3) is derived here based on recently published Ni data (Oller et al., 2014). Both values are protective for respiratory toxicity and carcinogenicity but differ in the application of toxicokinetic adjustments and cancer threshold considerations. Estimates of air Ni concentrations at the European regional scale were derived from the database of the European Environment Agency. The 50th and 90th percentile regional exposures were below both DNEL values. To assess REACH compliance at the local scale, measured ambient air data are preferred but are often unavailable. A tiered approach for the use of modelled ambient air concentrations was developed, starting with the application of the default EUSES model and progressing to more sophisticated models. As an example, the tiered approach was applied to 33 EU Ni sulphate producers' and downstream users' sites. Applying the EUSES model demonstrates compliance with a DNEL of 60ngNi/m(3) for the majority of sites, while the value of the refined modelling is demonstrated when a DNEL of 20ngNi/m(3) is considered. The proposed approach, applicable to metals in general, can be used in the context of REACH, for refining the risk characterisation and guiding the selection of risk management measures.

Inter-laboratory validation of bioaccessibility testing for metals.

Bioelution assays are fast, simple alternatives to in vivo testing. In this study, the intra- and inter-laboratory variability in bioaccessibility data generated by bioelution tests were evaluated in synthetic fluids relevant to oral, inhalation, and dermal exposure. Using one defined protocol, five laboratories measured metal release from cobalt oxide, cobalt powder, copper concentrate, Inconel alloy, leaded brass alloy, and nickel sulfate hexahydrate. Standard deviations of repeatability (sr) and reproducibility (sR) were used to evaluate the intra- and inter-laboratory variability, respectively. Examination of the sR:sr ratios demonstrated that, while gastric and lysosomal fluids had reasonably good reproducibility, other fluids did not show as good concordance between laboratories. Relative standard deviation (RSD) analysis showed more favorable reproducibility outcomes for some data sets; overall results varied more between- than within-laboratories. RSD analysis of sr showed good within-laboratory variability for all conditions except some metals in interstitial fluid. In general, these findings indicate that absolute bioaccessibility results in some biological fluids may vary between different laboratories. However, for most applications, measures of relative bioaccessibility are needed, diminishing the requirement for high inter-laboratory reproducibility in absolute metal releases. The inter-laboratory exercise suggests that the degrees of freedom within the protocol need to be addressed.

Derivation of PM10 size-selected human equivalent concentrations of inhaled nickel based on cancer and non-cancer effects on the respiratory tract.

Abstract Nickel (Ni) in ambient air is predominantly present in the form of oxides and sulfates, with the distribution of Ni mass between the fine (particle aerodynamic diameter < 2.5 µm; PM2.5) and coarser (2.5-10 µm) size-selected aerosol fractions of PM10 dependent on the aerosol's origin. When deriving a long-term health protective reference concentration for Ni in ambient air, the respiratory toxicity and carcinogenicity effects of the predominant Ni compounds in ambient air must be considered. Dosimetric adjustments to account for differences in aerosol particle size and respiratory tract deposition and/or clearance among rats, workers, and the general public were applied to experimentally- and epidemiologically-determined points of departure (PODs) such as no(low)-effect concentrations, for both cancer and non-cancer respiratory effects. This approach resulted in the derivation of threshold-based PM10 size-selected equivalent concentrations (modified PODs) of 0.5 µg Ni/m(3) based on workers' cancer effects and 9-11 µg Ni/m(3) based on rodent respiratory toxicity effects. Sources of uncertainty in exposure extrapolations are described. These are not reference concentrations; rather the derived PM10 size-selected modified PODs can be used as the starting point for the calculation of ambient air reference concentrations for Ni. The described approach is equally applicable to other particulates.

Oral bioaccessibility testing and read-across hazard assessment of nickel compounds.

In vitro metal ion bioaccessibility, as a measure of bioavailability, can be used to read-across toxicity information from data-rich, source substances to data-poor, target substances. To meet the data requirements for oral systemic toxicity endpoints under the REACH Regulation in Europe, 12 nickel substances underwent bioaccessibility testing in stomach and intestinal fluids. A read-across paradigm was developed based on the correlation between gastric bioaccessibility and in vivo acute oral toxicity. The oral LD50 values were well predicted by nickel release (R² = 0.91). Samples releasing <48% available nickel (mgNi released/mg available Ni × 100) are predicted to have an LD50 > 2000 mg/kg; while samples releasing > 76% available nickel are expected to have an LD50 between 300 and 2000 mg/kg. The hazard classifications (European Regulation on Classification, Labelling and Packaging of Chemical Substances and Mixtures) for all oral systemic endpoints were evaluated based on read-across from three source nickel compounds (sulfate, subsulfide, oxide). Samples releasing < 48% available nickel were read-across from nickel oxides and subsulfide. Samples releasing > 76% Ni were read-across from nickel sulfate. This assessment suggests that nickel chloride and dihydroxide should be less stringently classified and nickel sulfamate should receive a more stringent classification for oral systemic endpoints than currently assigned.

Acute oral toxicity of nickel compounds.

Acute oral toxicity studies were conducted on samples of nine unique nickel compounds and two complex materials to comply with the data and classification requirements of the new Registration, Evaluation, and Authorization of Chemicals Regulation (REACH) in Europe. The samples tested in this study confirmed the overall low oral toxicity of nickel substances and demonstrated a wide range of LD(50) values extending from 310 to >11,000 mg/kg. This variation highlights the differences in toxicological properties between various forms of nickel and underscores the importance of Ni(II) ion bioavailability in determining toxicity. The relative acute oral toxicity of the various nickel substances was found to be: nickel fluoride, nickel sulfate, nickel chloride, nickel acetate > nickel sulfamate > nickel hydroxycarbonate > nickel dihydroxide >> nickel subsulfide, nickel oxides, nickel ash, nickel mattes. Based on these data, four nickel compounds would receive a Category 4 acute toxicity classification according to the European Regulation on Classification, Labelling and Packaging of Chemical Substances and Mixtures (CLP), while the rest of the nickel substances tested fit the criterion for no classification. These data also provided the in vivo verification needed to perform read-across for additional oral toxicity endpoints and nickel substances.

Assessment of indirect human exposure to environmental sources of nickel: oral exposure and risk characterization for systemic effects.

This paper describes the indirect human exposure to Ni via the oral route for the regional scale in the EU, together with a method to assess additional local exposure from industrial emissions. The approach fills a gap in the generic REACH guidance which is inadequate for assessing indirect environmental exposure of metals. Estimates of regional scale Ni dietary intake were derived from Ni dietary studies performed in the EU. Typical and Reasonable Worst Case dietary Ni intakes for the general population in the EU were below the oral Derived No Effect Level (DNEL) of Ni sulfate for systemic effects. Estimates for the Ni dietary intake at the local scale take into account the influence of aerial Ni deposition and transfer from soil to crops grown near industrial plants emitting Ni. The additional dietary exposure via this local contribution was small. Despite the use of conservative parameters for these processes, this method may underestimate dietary exposure around older industrial sites because REACH guidance does not account for historical soil contamination. Nevertheless, the method developed here can also be used as a screening tool for community-based risk assessment, as it accounts for historical soil pollution. Nickel exposure via drinking water was derived from databases on Ni tap water quality. A small proportion of the EU population (<5%) is likely to be exposed to tap water exceeding the EU standard (20 µg Ni/l). Taking into account the relative gastrointestinal absorption of Ni from water (30%) versus from solid matrices (5%), water intake constitutes, after dietary intake, the second most important pathway for oral Ni intake. Incidental ingestion of Ni from soil/dust at the regional scale, and also at the local scale, was low in comparison with dietary intake.

The nickel ion bioavailability model of the carcinogenic potential of nickel-containing substances in the lung.

The inhalation of nickel-containing dust has been associated with an increased risk of respiratory cancer in workplaces that process and refine sulfidic nickel mattes, where workers are exposed to mixtures of sulfidic, oxidic, water-soluble, and metallic forms of nickel. Because there is great complexity in the physical and chemical properties of nickel species, it is of interest which specific nickel forms are associated with carcinogenic risk. A bioavailability model for tumor induction by nickel has been proposed, based on the results of animal inhalation bioassays conducted on four nickel-containing substances. The nickel ion bioavailability model holds that a nickel-containing substance must release nickel ions that become bioavailable at the nucleus of epithelial respiratory cells for the substance to be carcinogenic, and that the carcinogenic potency of the substance is proportional to the degree to which the nickel ions are bioavailable at that site. This hypothesis updates the nickel ion theory, which holds that exposure to any nickel-containing substance leads to an increased cancer risk. The bioavailability of nickel ions from nickel-containing substances depends on their respiratory toxicity, clearance, intracellular uptake, and both extracellular and intracellular dissolution. Although some data gaps were identified, a weight-of-evidence evaluation indicates that the nickel ion bioavailability model may explain the existing animal and in vitro data better than the nickel ion theory. Epidemiological data are not sufficiently robust for determining which model is most appropriate, but are consistent with the nickel ion bioavailability model. Information on nickel bioavailability should be incorporated into future risk assessments.

Incorporation of particle size differences between animal studies and human workplace aerosols for deriving exposure limit values.

Inhalation animal studies usually employ homogeneous aerosols of small particle diameter. By contrast, workers are usually exposed to coarser and more heterogeneous aerosols. The particle size distribution of an aerosol will determine the deposited fraction of inhaled particles in the various regions of the respiratory tract in rodents and humans. The deposited, and subsequently retained, doses in these regions correlate closely with long-term toxic effects. Yet, differences in deposited doses between animals and humans due to particle size differences of aerosols have not been consistently taken into account in risk assessment. This paper describes an approach to calculate equivalent human concentrations (EHC) for respiratory tract effects after inhalation using workplace particle size information. Worker's exposure to the EHC results in the same deposited dose in the respiratory tract as achieved in animals exposed to the experimental particle size distribution. Example data for nickel compounds demonstrate that exposure levels used in the rat studies are equivalent to 4-11-fold higher levels of human workplace exposures. This approach is equally applicable to other metal/inorganic particulates that exert adverse effects on the respiratory tract after inhalation. Dosimetric extrapolation should be a first step in the derivation of limit values based on animal local respiratory effects.

Temperature effect on nickel release in ammonium citrate.

Leaching in ammonium citrate has been extensively used to assess the fraction of water-soluble nickel compounds present in nickel producing and using workplace aerosols. Leaching in ammonium citrate according to the first step of the Zatka protocol was found to overestimate the water-soluble nickel fraction by more than ten-fold compared to synthetic lung fluid (37 degrees C), when nickel carbonate and subsulfide were present. These results suggest that exposure matrices based on this method should be reexamined. Leaching studies of refinery particles are needed to further clarify this important issue.

Comparison of nickel release in solutions used for the identification of water-soluble nickel exposures and in synthetic lung fluids.

Chemical speciation of workplace nickel exposures is critical because nickel-containing substances often differ in toxicological properties. Exposure matrices based on leaching methods have been used to ascertain which chemical forms of nickel are primarily associated with adverse respiratory effects after inhalation. Misjudgments in the relative proportion of each of the main fractions of nickel in workplace exposures could translate into possible misattributions of risk to the various forms of nickel. This preliminary study looked at the efficiency of the first step of the Zatka leaching method for accurately assessing the 'water-soluble' fraction of several substances present in nickel production operations, compared to leaching in synthetic lung fluid. The present results demonstrate that for nickel sulfate or chloride, the current Zatka solution is adequate to assess the 'water-soluble' fraction. However, when sparingly water-soluble compounds like nickel carbonates or water-insoluble substances like nickel subsulfide and fine metallic nickel powders are present, the first step of the Zatka method can greatly over estimate the amount of nickel that could be released in pure water. In contrast, the releases of nickel from nickel carbonate, nickel subsulfide, and nickel metal powders in pure water are consistent with their releases in synthetic lung fluid, indicating that deionized water is a better leaching solution to estimate the biologically relevant 'water-soluble' nickel fraction of workplace exposures. Exposure matrices relying mostly on the Zatka speciation method to estimate the main forms of nickel need to be re-evaluated to account for any possible misattributions of risk.

Inhalation carcinogenicity study with nickel metal powder in Wistar rats.

Epidemiological studies of nickel refinery workers have demonstrated an association between increased respiratory cancer risk and exposure to certain nickel compounds (later confirmed in animal studies). However, the lack of an association found in epidemiological analyses for nickel metal remained unconfirmed for lack of robust animal inhalation studies. In the present study, Wistar rats were exposed by whole-body inhalation to 0, 0.1, 0.4, and 1.0 mg Ni/m(3) nickel metal powder (MMAD=1.8 microm, GSD=2.4 microm) for 6 h/day, 5 days/week for up to 24 months. A subsequent six-month period without exposures preceded the final euthanasia. High mortality among rats exposed to 1.0 mg Ni/m(3) nickel metal resulted in the earlier termination of exposures in this group. The exposure level of 0.4 mg Ni/m(3) was established as the MTD for the study. Lung alterations associated with nickel metal exposure included alveolar proteinosis, alveolar histiocytosis, chronic inflammation, and bronchiolar-alveolar hyperplasia. No increased incidence of neoplasm of the respiratory tract was observed. Adrenal gland pheochromocytomas (benign and malignant) in males and combined cortical adenomas/carcinomas in females were induced in a dose-dependent manner by the nickel metal exposure. The incidence of pheochromocytomas was statistically increased in the 0.4 mg Ni/m(3) male group. Pheochromocytomas appear to be secondary to the lung toxicity associated with the exposure rather than being related to a direct nickel effect on the adrenal glands. The incidence of cortical tumors among 0.4 mg Ni/m(3) females, although statistically higher compared to the concurrent controls, falls within the historical control range; therefore, in the present study, this tumor is of uncertain relationship to nickel metal exposure. The lack of respiratory tumors in the present animal study is consistent with the findings of the epidemiological studies.

Oral carcinogenicity study with nickel sulfate hexahydrate in Fischer 344 rats.

Until now, existing data on the oral carcinogenicity of nickel substances have been inconclusive. Yet, the assessment of oral carcinogenicity of nickel has serious scientific and regulatory implications. In the present study, nickel sulfate hexahydrate was administered daily to Fischer 344 rats by oral gavage for 2 years (104 weeks) at exposure levels of 10, 30 and 50 mg NiSO(4).6H(2)O/kg. This treatment produced a statistically significant reduction in body weight of male and female rats, compared to controls, in an exposure-related fashion at 30 and 50 mg/kg/day. An exposure-dependent increase in mortality was observed in female rats. However, the overall study survival rate (males and females) was at least 25 animals per group (compliant with OECD guidelines) in the treated animals. Daily oral administration of nickel sulfate hexahydrate did not produce an exposure-related increase in any common tumor type or an increase in any rare tumors. One tumor type was statistically increased in a nickel sulfate-treated group compared to the study controls (keratoacanthoma in the 10 mg NiSO(4).6H(2)O/kg/day males), but there was no exposure-response relationship for this common tumor type. This study achieved sufficient toxicity to reach the Maximum Tolerated Dose (MTD) while maintaining a sufficiently high survival rate to allow evaluation for carcinogenicity. The present study indicated that nickel sulfate hexahydrate does not have the potential to cause carcinogenicity by the oral route of exposure in the Fischer 344 rat. Data from this and other studies demonstrate that inhalation is the only route of exposure that might cause concern for cancer in association with nickel exposures.

Lack of micronuclei formation in bone marrow of rats after repeated oral exposure to nickel sulfate hexahydrate.

Workplace exposures to mixtures of nickel compounds have been associated with excess respiratory cancer risk. Animal studies with individual nickel compounds indicate that not all nickel substances have the same potency or potential to induce tumors. The bioavailability of nickel ions at critical cellular sites seems to be important to determine the potential of a substance to induce tumors in animals, but much less is understood about the exact nature (genotoxic or non-genotoxic) of the nickel effects. Within many regulatory frameworks (e.g., European Union), substances are classified for mutagenicity based on the available data and this classification will often influence the mode of action assigned to carcinogenic substances and the way in which risk assessment will be conducted. The objective of this study was to evaluate the ability of nickel sulfate hexahydrate to induce micronuclei in polychromatic erythrocytes (PCEs) in rat bone marrow. This study was conducted according to OECD and EU protocol guidelines. In the dose range-finding assays, the maximum tolerated dose was estimated to be 500 mg/kg/day. The doses used in the micronucleus assay were 125, 250, and 500 mg/kg/day. At least 2000 PCEs per animal were analyzed for micronuclei in PCEs. Cytotoxicity was assessed by scoring a minimum of 500 consecutive total polychromatic (PCE) and normochromatic (NCE) erythrocytes (PCE/NCE ratio). Nickel sulfate hexahydrate did not induce statistically significant increases in micronucleated PCEs at any dose examined. The negative results in the present study contribute significantly to the weight of evidence evaluation of the mutagenicity (chromosomal level) of nickel substances. These results are consistent with a non-genotoxic mode of action for soluble nickel that could explain the enhancement of cancer risk seen among refinery workers with mixed exposures and its lack of carcinogenicity in animal studies with single exposures.

Respiratory cancer risks associated with low-level nickel exposure: an integrated assessment based on animal, epidemiological, and mechanistic data.

Increased lung and nasal cancer risks have been reported in several cohorts of nickel refinery workers, but in more than 90% of the nickel-exposed workers that have been studied there is little, if any evidence of excess risk. This investigation utilizes human exposure measurements, animal data from cancer bioassays of three nickel compounds, and a mechanistic theory of nickel carcinogenesis to reconcile the disparities in lung cancer risk among nickel-exposed workers. Animal data and mechanistic theory suggest that the apparent absence of risk in workers with low nickel exposures is due to threshold-like responses in lung tumor incidence (oxidic nickel), tumor promotion (soluble nickel), and genetic damage (sulfidic nickel). When animal-based lung cancer dose-response functions for these compounds are extrapolated to humans, taking into account interspecies differences in deposition and clearance, differences in particle size distributions, and human work activity patterns, the predicted risks at occupational exposures are remarkably similar to those observed in nickel-exposed workers. This provides support for using the animal-based dose-response functions to estimate occupational exposure limits, which are found to be comparable to those in current use.