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Bioelution tests measure in vitro the release of metal ion in surrogate physiological conditions (termed "bioaccessibility") and estimate the potential bioavailability relative to that of a known reference metal substance. Bioaccessibility of cobalt ion from twelve cobalt substances was tested in three artificial lung fluids (interstitial, alveolar and lysosomal) to gather information about the substances' fate and potential bioavailability in the respiratory tract after inhalation. The results can be used as one line of evidence to support grouping and read-across for substances lacking in vivo data, and where in vivo testing is not readily justifiable. Strong differences were observed in the dissolution behaviour of the substances in the different fluids, with the cobalt substances generally being less soluble in neutral pH fluids and more soluble in the acidic pH fluid. The resulting database, presented with its strengths and limitations, was used to support the formulation of an initial grouping of these cobalt substances into three categories.

Bioelution, the measuring of in vitro metal ion release from metals or metal compounds in simulated body fluids, can be used as a tool to measure bioaccessibility of metals and metal compounds, and as such provide an estimate of their bioavailability. Comparable bioelution results can allow grouping of substances within a “metal” family. By referring to toxicity data on a metal substance (reference substance) within the group, predictions on the hazard of the other substances in the group can be established. This paper discusses how bioelution testing of metals and metal compounds can be used as an alternative to animal testing for obtaining basic information on their potential toxicity, while allowing compliance with strict information requirements. Two human health hazard endpoints are used to illustrate how bioelution can become part of a testing programme and in particular, target the requirement for new studies and minimise the need for animal testing. In these cases, it is shown how bioelution can be used to predict the hazard of several indium compounds as a first screening.

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.

The oral bioaccessibility of copper alloys and pure metals was assessed using in vitro methods with synthetic saliva and gastric fluid. The metal-specific migration rates from polished alloy surfaces are higher in gastric (pH 1.5) than in saliva fluid (pH 7.2). In both media, migrations are higher for lead than for other metals. The bioaccessible metal concentrations in massive copper alloys, after 2 h in gastric fluid, was only0.01%-0.18%, consistent with the low surface reactivity of copper alloys (defined as 1 mm spheres). The average metal-specific migrations of cobalt, copper, nickel and lead from most of the tested copper alloys in gastric media are comparable to the ones from their pure metals. The data further show that the bioaccessibility of metals in massive copper alloys primarily depends on the bioelution medium, the exposed surface area and the composition of the alloy. The tested copper alloys show only limited evidence for influence of alloy surface microstructure. This is contrary to findings for other alloys such as stainless steel. Additional investigations on other copper alloys could allow to further refine these conclusions. These findings are useful for establishing the hazard and risk profile of copper alloys following oral exposure.

P.J. Van den Brink et al., The United Nations Sustainability Development Goals (SDGs) have been established to end poverty, protect the planet and ensure prosperity for all. Delivery of the SDGs will require a healthy and productive environment. An understanding of the impacts of chemicals, which can negatively impact environmental health, is therefore essential to the delivery of the SDGs. However, current research on and regulation of chemicals in the environment tends to take a simplistic view and does not account for the complexity of the real world, which inhibits the way we manage chemicals. There is therefore an urgent need for a step-change in the way we study and communicate h the impacts and control of chemicals in the natural environment. To do this requires the major research questions to be identified so that resources are focused on questions that really matter. In this paper, we present the findings of a horizon scanning exercise to identify research priorities of the European environmental science community around chemicals in the environment. Using the key questions approach, we identified 22 questions of priority. These questions covered: overarching questions around which chemicals we should be most concerned about and where, impacts of global megatrends, protection goals and sustainability of chemicals; the development and parameterisation of assessment and management frameworks; and mechanisms to maximise the impact of the research. The research questions identified in this paper provide a first-step in the path forward for the research, regulatory and business communities to better assess and manage chemicals in the natural environment., We would like to thank the financial support provided by Baylor University, Tony and Donna Robert, the University of York, and the US Environmental Protection Agency.

Several IT tools have been developed to facilitate the evaluation of complex inorganic materials, with the aim to support the assessor at specific steps of the assessment, such as the Metals Classification Tool (MeClas) for hazard identification and classification, or MEASE and specific environmental release categories (SPERCs) that generate exposure estimates. In addition, several tools have been made available by the scientific, regulatory, and industry communities to consider metal specificities such as bioavailability in the environment (Biomet, PNEC.Pro, M-BAT) and fate (TICKET-UWM). All these tools, easily accessible, are based on the current knowledge and are regularly updated to take into account new metal science and user-friendliness. The chapter provides a general overview of these tools as well as their principal features.

The intrinsic variability in chemical composition and the sometimes unknown speciation of inorganic UVCBs (Unknown or Variable composition, Complex reaction products, or Biological materials) result in uncertainties during their assessment, requiring the development of a specific approach. The strategy for the assessment focuses on capturing the variability in composition using the knowledge of processes and input materials, defining the ranges in composition as well as the chemical speciation where applicable, compiling the hazard profiles of the constituents and classifying the UVCB based on the combination of these data. Elemental concentrations of the UVCB constituents are usually measured due to their economic value, allowing to document the variability in composition. Speciation, preset by the input material and process is not routinely quantified. Where the speciation of the constituent is unknown, the speciation with the worst-case classification can be taken forward for the calculation of the UVCB classification. For the risk assessment, the hazards of each constituent are assessed and the corresponding effect values (e.g. PNEC, DNEL) taken forward where a hazard is identified. Workplace monitoring and environmental release data as well as metal-specific models are used in exposure assessment. The potential combined exposure and toxicity of the UVCB constituents are assessed in a tiered way, starting from the conservative summation of the RCRs, further refined with additional information.

Complex inorganic materials have specific (eco-) toxic properties conveyed by the metals they are containing. The main principles governing the mechanisms of the toxicity of metals can therefore be applied when assessing complex inorganic materials, particularly in relation to the rate and extent to which these materials can produce soluble (bio)available ionic and other metal-bearing species (e.g. metal complexes). This chapter describes the key mechanistic aspects to consider when managing the human health and environmental risks of such materials, such as bioavailability, speciation, particle size, essentiality, or natural background. It also describes briefly the endpoints requiring the consideration of metal specificities when assessing the underlying mechanisms of toxicity.

Accurate identification and evaluation of exposure/emissions along the entire life cycle of complex inorganic materials is crucial to ensure that the potentially associated environmental and health risks are properly managed. The evaluation of exposure/emissions shall cover the workplace (occupational exposure), the different environmental compartments (environmental exposure), the general population exposed to such materials indirectly via air, food, or drinking water or directly as potential consumers of preparations or goods containing such materials. This chapter describes the key elements of relevance when assessing exposure to complex inorganic materials (variability, speciation, physical form), including some general principles aiming at preventing/reducing exposure/emissions.

The appropriate assessment of the human health hazards of complex inorganic materials is required to ensure their adequate risk management. This requires that the collection of data fulfils information requirements outlined in different chemicals management systems and identifies gaps in the knowledge of the material. Toxicity data on complex inorganic materials allowing to fulfil these human health information requirements and derive dose–responses/effect levels are usually scarce. Although testing could be theoretically envisaged to complete data gaps, the number of complex inorganic materials to be assessed would have significant implications for animal welfare and represent a disproportionate burden. For some materials like the Unknown or Variable composition, Complex reaction products or Biological materials (UVCBs), the variability will also prevent selecting a representative sample. The assessment will therefore often be based on the constituents of the complex materials. This chapter will discuss some alternatives to collect hazard information, like grouping and read-across of complex materials, the use of data on the constituents, and present recent refinements, illustrated with examples that can be of help.

Sir,We are grateful for the opportunity to answer the letter by C.G. Elinder and G.F. Nordberg (2017) that raises interesting points. To meet the requested format of this response, we included here...

The assessment of environmental exposure and risks associated with the production or use of a substance on an industrial site includes the estimation of the releases to the environment. In the absence of measured release data on the specific substance, a risk assessor would rely on default release factors to the environmental compartments as developed in international, national, or regional context. Because a wide variety of substances, processes, and uses has to be covered, default release factors are as a rule conservative, usually leading to significant overprediction of releases and hence to overpredicted environmental exposure concentrations and risks. In practice, unrealistic and worst-case predictions do not support a more efficient management of releases and risk. The objective of this article is to propose a more realistic approach to characterize the environmental releases from manufacture, processing, and downstream uses of the metals and their compounds. Although developed in the European Union (EU), this approach can also be used in other regions and in other chemical management systems addressing metals. A database consisting of more than 1300 recent (1993–2010), site-specific measured release factors to air and water of 18 different metals from various EU Member States was compiled and used to calculate average and reasonable worst-case release factors for multiple metal manufacture and industrial use processes. The parameters influencing releases to water were found to depend predominantly on life cycle step (manufacture and/or use), the sector and/or the solid–water partition coefficient (Kd). The release factors can be used as advanced tier instrument in environmental safety assessments, increasing the realism of the estimates while still keeping a sufficient level of conservatism. Integr Environ Assess Manag 2014;10:529–538. © 2014 SETAC

Background: Cadmium (Cd) is abundantly documented as a metal mainly affecting tubular function both in workers and in the general population indirectly exposed via the environment. Results from epidemiological studies linking Cd exposure and risk of progression to chronic kidney disease (CKD) are, however, conflicting. Objectives: To perform a systematic review of the association between Cd exposure and CKD. Methods: A systematic appraisal of publications found in MEDLINE (1946–2014), EMBASE (1974–2012) and an in-house database (1986–2013) was conducted. Additional studies were searched for by contacting experts and checking reference lists. Search terms used key and text words. No language restriction was applied. Cohort, case–control and case-series with follow-up including individual and objective assessment of occupational or environmental exposure were eligible. Studies were selected and data extracted by two independent reviewers using predefined forms. Study characteristics and results were extracted to structured tables. Synthesis was qualitative and results appraised with causality criteria. Results: Thirty-four exposed groups, totaling more than 3000 participants, were eligible. Overall, results disclosed no convincing evidence supporting a risk of progression to CKD in populations exposed to Cd. Lack of information about methods, risk of bias and heterogeneity were identified as limitations and precluded conducting a meta-analysis. Publication bias did not appear as a major problem. Conclusions: This qualitative systematic review does not support the contention that human exposure to Cd leads to progressive CKD. Abbreviations: AQC: analytical quality control; A1MG: a1-microglobulin; B2MG: b2-microglobulin; Cd: cadmium; Cd-B: cadmium in blood; Cd-kidney: Cd in kidney; Cd-liver: Cd in liver; Cd-U: cadmium in urine; CI: confidence interval; ClC5: chloride channel 5; CKD: chronic kidney disease; CKD-EPI: CKD Epidemiology Collaboration; CKDu: chronic kidney disease of unknown origin; ESRD: end-stage renal disease (kidney failure treated by dialysis or transplantation); GFR: glomerular filtration rate; eGFR: estimated glomerular filtration rate; GM: geometric mean; GSD: geometric standard deviation; HMW: high-molecular-weight; ICD: International Classification of Diseases; KDIGO: Kidney Disease Improving Global Outcomes; LMW: low-molecular-weight; MDRD: Modification of Diet in Renal Disease; mGFR: measured GFR; NA: non-applicable; NAG: N-acetyl-b-D-glucosaminidase; NI: no information; ND: not done; ns: non-significant; P: plasma; RBP: retinol-binding protein; RRT: renal replacement therapy; S: serum; SD: standard deviation; SMR: standardized mortality ratio; U: urine

OBJECTIVE: To investigate the possible association between the body burden of dioxin-like compounds and endometriotic disease. DESIGN: Case-control study. SETTING: Gynecology ward in a university hospital. PATIENT(S): Seventy-one women with peritoneal endometriosis (n = 25) or deep endometriotic (adenomyotic) nodules (n = 25) and controls (n = 21). INTERVENTION(S): Collection of 200 mL of blood (fasted) and face-to-face interview. MAIN OUTCOME MEASURE(S): Assessment of dioxin (PCDD), furan (PCDF), and dioxin-like PCB serum concentrations (picograms toxic equivalent [TEQ]/g lipids). RESULT(S): Age and body mass index were traced by linear multiple regression as determinants of total TEQ levels. After standardization for these variables (30 years and 22.5 kg/m2), the mean TEQ levels were 24.21 (controls), 30.62 (peritoneal endometriosis), and 37.60 (deep endometriotic [adenomyotic] nodules) pg TEQ/g lipids. Logistic regression analysis indicated a significantly increased risk of deep endometriotic (adenomyotic) nodules (odds ratio [OR], 3.3; 95% confidence interval [CI], 1.4-7.6) for an increment of 10 pg in total TEQ levels/g lipids. An increased risk was also found for peritoneal endometriosis (OR, 1.9; 95% CI, 0.9-3.8) for total TEQ levels and for dioxins alone (OR, 3.2; 95% CI, 1.0-9.9). CONCLUSION(S): The results provide the first epidemiological evidence of an association between increased PCDD/PCDF and PCB body burden and endometriosis.

Environmental chemicals with oestrogen-like activity are suspected aetiological factors of endometriosis. In animal experiments, cadmium was recently shown to possess oestrogen-like properties. In the frame of a case-control study designed to investigate environmental risk factors for endometriosis, we compared cadmium urinary excretion (CdU) and blood concentration in 59 patients with peritoneal endometriosis, deep endometriotic (adenomyotic) nodules of the recto-vaginal septum and controls. After standardisation for age (30 years) and smoking status, the mean levels of cadmium in urine were (geometric mean [geometric S.D.]) 0.25 [1.50], 0.29 [1.76] and 0.26 [1.46] microg/g creatinine, respectively. Cadmium concentrations in blood did not differ among the three groups. These data, therefore, do not support a role for cadmium in the onset or the growth of endometriosis or deep endometriotic (adenomyotic) nodules of the recto-vaginal septum.

The objective of the study was to examine the influence of cobalt exposure on lung function changes in workers from a cobalt-producing plant in a health monitoring program implemented between 1988 and 2001. A total of 122 male workers with at least 4 (median = 6) lung function tests (FEV(1) and FVC) during the follow-up period were assessed longitudinally. Cobalt exposure significantly decreased over the follow-up period, as reflected by the measurements in air and urine. The possible association of spirometric changes with cobalt exposure was examined by a random coefficients model, taking into account other potential influential variables, such as smoking, age, previous respiratory illness, exposure to other lung toxicants, or the presence of glutamate in position 69 in the HLA-DP beta-chain, an HLA polymorphism possibly associated with hard-metal-induced lung diseases. The main finding of the follow-up study was that cobalt exposure contributed to a decline in FEV(1) over time, and only in association with smoking. No influence of glutamate in position 69 in the HLA-DP beta-chain polymorphism was detected. Although the amplitude of the additional FEV(1) decrement associated with smoking exposure was relatively small (< 20%) compared with the expected decline in a non-cobalt-exposed smoker, the results indicate that further efforts to reduce cobalt exposure and to encourage workers to quit smoking are still warranted.

BACKGROUND: Exposure to cadmium fumes or dusts has been associated with an increased risk of lung cancer and the characterisation of the genotoxic potential of cadmium compounds is, among other possible mechanisms, an important element in the assessment of the carcinogenic hazard of the element. While there is some evidence that in experimental systems, cadmium compounds may exert genotoxic effects, the results of the epidemiological studies having examined cytogenetic endpoints in humans exposed to cadmium appear conflicting. Therefore, a systematic review was undertaken to assess whether a cytogenetic effect of cadmium exposure is supported by the studies with the strongest design. METHODS: The relevant literature was identified through several databases and assessed with a check-list by two reviewers. Causes of heterogeneity between studies were looked for. Results were extracted and the strength of the evidence was evaluated with causality criteria. RESULTS: No studies met the criteria for being considered as very convincing. Several factors were identified that could explain contradictory findings (small sample size, selection bias, insufficient characterisation of exposure, lack of consideration of confounders) but their actual impact could not be conclusively assessed with the published information. Importantly, it should be recognised that the absence of a clear mechanism for the cytogenetic action of cadmium compounds did not allow to select the most appropriate endpoint to be examined. CONCLUSIONS: No clear association between cadmium exposure and cytogenetic endpoint appeared but no definite conclusion can be drawn from the existing studies in humans. Future research efforts should mainly focus on experimental studies to understand how cadmium compounds could produce genotoxic/carcinogenic effects, in order to target the most relevant endpoint to be examined in humans.

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.

This review considers the development of the regulatory process for metals in the European Union (Regulation for Registration, Evaluation, Authorisation and Restriction of Chemicals, REACH). The manner in which the REACH process was developed, its history, and the relative involvement of government and industry are examined. The problems involved in setting up the system and the steps in optimisation are considered. One of the major difficulties in the development of the REACH mechanism was incorporating the fact that many metals are essential elements, which is not a factor that most toxicological examinations consider. How the REACH process evolved to deal with these problems and how the mechanisms were put in place to overcome them is examined. Looking specifically at examples of industry working with academia, one needs to consider how a risk assessment can be developed and submitted in a timely and successful fashion.

The aim of this study was to estimate occupational exposure to inhalable wood dust by country, industry, the level of exposure and type of wood dust in 25 member states of the European Union (EU-25) for the purposes of hazard control, exposure surveillance and assessment of health risks. National labour force statistics, a country questionnaire (in 15 member states, EU-15), a company survey (in Finland, France, Germany and Spain), exposure measurements (from Denmark, Finland, France, Germany, The Netherlands and the United Kingdom) and expert judgements were used to generate preliminary estimates of exposure to different types of wood dust. The estimates were generated according to industrial class (six wood industries, four other sectors) and level of exposure (five classes). These estimates were reviewed and finalized by national experts from 15 member states. Crude estimates were generated also for 10 new member states (EU-10). The basic data and final estimates were included in the WOODEX database. In 2000-2003, about 3.6 million workers (2.0% of the employed EU-25 population) were occupationally exposed to inhalable wood dust. Of those, construction employed 1.2 million exposed workers (33%), mostly construction carpenters. The numbers of exposed workers were 700,000 (20%) in the furniture industry, 300,000 (9%) in the manufacture of builders' carpentry, 200,000 (5%) in sawmilling, 150,000 (4%) in forestry and100,000 in other wood industries. In addition, there were 700,000 exposed workers (20%) in miscellaneous industries employing carpenters, joiners and other woodworkers. The numbers of exposed workers varied by country ranging from3,000 in Luxembourg and Malta to 700,000 in Germany. The highest exposure levels were estimated to occur in the construction sector and furniture industry. Due to limited exposure data there was considerable uncertainty in the estimates concerning construction woodworkers. About 560,000 workers (16% of the exposed) may be exposed to a level exceeding 5 mg m(-3). Mixed exposure to more than one species of wood and dust from wooden boards was very common, but reliable data on exposure to different species of wood could not be retrieved. This kind of assessment procedure integrating measurement data, company data, country-specific data and expert judgement could also serve as one model for the assessment of other occupational exposures.

Peritoneal endometriosis (PE) and deep endometriotic nodules (DEN) are gynecological diseases recently shown to be associated with elevated serum concentrations of organochlorines. The objective of the present study was to compare risk factors associated with both forms of the disease, with a particular attention to potential sources of organochlorine exposure. This matched case-control study with prospective recruitment included 88 triads (PE-DEN-control). All women were face-to-face interviewed with a standardized questionnaire, and serum dioxin and polychlorinated biphenyl measurements were available for 58 of them. Alcohol consumption (odds ratio (OR): 5.82 [confidence interval at 95% (95%CI) 1.20-28.3]) in DEN and low physical activity at work for DEN (OR: 4.58 [95%CI 1.80-11.62]) and PE (OR: 5.61 [95%CI 1.90-16.60]) were traced as significant risk factors. Organochlorine-related factors (use of tampons, occupational or environmental exposure) were not related to the disease. The current consumption of foodstuffs that were more likely to contribute to organochlorine body burden did not differ among the groups. Only some of these fatty foodstuffs (marine fish, pig meat) were traced by multiple regression analysis as significant determinants of organochlorine body burden, explaining only a small fraction (20%) of the interindividual variation of organochlorine body burden. We conclude that PE and DEN share similar patterns of risk or protective factors.

Objectives: Cadmium (Cd) and lead (Pb) have been demonstrated to exert endocrine disrupting activities. Their possible role in endometriosis, an oestrogen-dependent disease, is unknown. Methods: We compared cadmium urinary excretion (CdU) and blood concentration of cadmium (CdB) and lead (PbB) in 119 patients with peritoneal endometriosis and/or deep endometriotic (adenomyotic) nodules of the rectovaginal septum and 25 controls. Results: The mean levels of cadmium in urine and blood did not differ among the groups. Women suffering from endometriotic diseases showed lower levels of PbB than controls. Conclusions: These data do not support a role for cadmium in the onset or the growth of endometriotic diseases but suggest a possible relationship with lead.

Cadmium (Cd) and its compounds were classified as "carcinogenic to humans (Group 1)" by IARC in 1993. The observation of an increased number of lung cancers in a U.S. cohort of cadmium-exposed workers and the finding of tumors in animals exposed to various cadmium compounds apparently played an important role in this assessment. Since this evaluation, several cohorts of cadmium exposed workers have been updated and some additional data regarding environmental exposure to cadmium and cancer risk have been published. The main purpose of this systematic review was to examine whether inclusion of the studies that were not available for the 1993 evaluation might change the overall assessment of the carcinogenic potential of cadmium compounds. A second objective was to examine whether the recent studies are qualitatively better than the older ones and whether they should receive more weight in this assessment. A third issue was to investigate whether a competing effect between nonmalignant respiratory disease (NMRD) and lung cancer may have affected the results for lung cancer in occupationally exposed cohorts. Overall, considering the results of the most recent studies does not suggest that the effect of cadmium on lung cancer increases with improvement of the study design but points to a lower relative risk in the groups exposed to cadmium in the absence of arsenic and nickel. No evidence was found to support the hypothesis that NMRD represents a competing cause of death reducing the mortality from lung cancer. The association between cadmium exposure and prostate cancer was not confirmed in the latest available updates. Studies in environmentally exposed populations do not indicate an increased relative risk of cancer.

OBJECTIVE—To integrate recent understandings of the mechanisms of genotoxicity and carcinogenicity of the different cobalt compounds. METHOD—A narrative review of the studies published since the last IARC assessment in 1991 (genotoxicity, experimental carcinogenesis, and epidemiology). RESULTS—Two different mechanisms of genotoxicity, DNA breakage induced by cobalt metal and especially hard metal particles, and inhibition of DNA repair by cobalt (II) ions contribute to the carcinogenic potential of cobalt compounds. There is evidence that soluble cobalt (II) cations exert a genotoxic and carcinogenic activity in vitro and in vivo in experimental systems but evidence in humans is lacking. Experimental data indicate some evidence of a genotoxic potential for cobalt metal in vitro in human lymphocytes but there is no evidence available of a carcinogenic potential. There is evidence that hard metal particles exert a genotoxic and carcinogenic activity in vitro and in human studies, respectively. There is insufficient information for cobalt oxides and other compounds. CONCLUSION—Although many areas of uncertainty remain, an assessment of the carcinogenicity of cobalt and its compounds requires a clear distinction between the different compounds of the element and needs to take into account the different mechanisms involved. Keywords: cobalt; DNA breakage; inhibition of DNA repair