In July 2020 NiPERA turned 40! The metals industry now knows NiPERA Inc. as the leading scientific organization on nickel-specific human health and environmental research. During our 40 years of service, NiPERA has increased awareness of the current state of the science on the potential health and environmental effects associated with the production, use, and disposal of nickel. Over the past four decades the specialist team of NiPERA scientists, past and present, has generated an extensive body of scientific work that has enhanced our understanding of both nickel toxicity and safe use. Much of it has provided the basis for regulations that are protective of human health and the environment.
“Thanks to our scientists past and present, we have the scientific knowledge to understand the potential health and environmental effects of nickel. This ensures that nickel can be produced, used and disposed of safely. Its amazing properties can be employed with confidence in appropriate applications.”
Adriana Oller, Executive Director, NiPERA Inc.
Why NiPERA was formed?
The idea for an independent nickel research organization arose from several nickel refinery company physicians and health & safety officers. They wanted to collaborate to better understand the health effects associated with workplace exposures to nickel substances and to make their operations safer for workers. The initial focus was on human health and respiratory disease.
Increased lung and nasal cancer risks associated with exposure to nickel aerosols in sulfidic nickel refining and processing operations had been first reported in 1958. But little was known about what chemical forms of nickel were involved and at what levels. It was important for the nickel producers to have a sound scientific basis to ensure appropriate workplace health and safety measures.
This led to the establishment of NiPERA (Nickel Producers Environmental Research Association) in July 1980.
Seminal epidemiological study
One of the first tasks for the newly formed NiPERA was to identify the knowledge gaps and fund epidemiological studies to fill them.
In the 1980s, an early initiative for NiPERA was to participate in a major epidemiological study of around 80,000 workers in ten nickel production plants. The goal was to fill the gaps in understanding the risks of cancer associated with nickel exposures in various chemical forms. The study brought together partners from North America and Europe – the US Environmental Protection Agency; the Commission of European Communities; Energy, Mines, and Resources Canada; National Health and Welfare Canada and the Ontario Ministry of Labour. It was led by eminent epidemiologist Sir Richard Doll. Published in 1990, the study concluded that there was no evidence that metallic nickel was associated with increased lung and nasal cancer risks but that several other chemical forms of nickel could result in respiratory carcinogenicity after inhalation. The findings of this study and the updates that followed, have provided a sound scientific basis for subsequent protective occupational health regulations.
“The main conclusion that can be reached from the examination of the ten cohorts is that it appears that more than one form of nickel gives rise to lung and nasal cancer. Although much of the respiratory cancer risk seen among the nickel refinery workers could be attributed to exposure to a mixture of oxidic and sulfidic nickel at very high concentrations, exposure to large concentrations of oxidic nickel in the absence of sulfidic nickel was also associated with increased lung and nasal cancer risks. There was also evidence that soluble nickel exposure increased the risk of these cancers and that it may enhance risks associated with exposure to less soluble forms of nickel. There was no evidence that metallic nickel was associated with increased lung and nasal cancer risks, and no substantial evidence was obtained to suggest, that occupational exposure to nickel or any of its compounds was likely to produce cancers elsewhere than in the lung or nose.”
Doll et al. 1990, Report of the International Committee on Nickel Carcinogenesis
NiDI and NiPERA Merger
During the late 1990’s NiPERA’s mandate grew to include a more comprehensive approach to regulatory actions and the environmental toxicology effects of nickel and its compounds.
During this period the global nickel industry decided to streamline its representation. Since the 1980s the nickel industry had been represented by separately incorporated entities: the Nickel Development Institute (NiDI), NiPERA, and an ad hoc organization in Europe known as the European Nickel Group (ENiG). Upon reflection it was obvious that while the organizations were operated separately they shared a broadly common company membership.
NiDI was responsible for nickel market development, while the science-based “license to produce and market” nickel aspects were handled by NiPERA. NiPERA focused on regulatory risk assessment (i.e., the science of determining safe exposure values, such as drinking water standards). In addition, the European Nickel group (ENiG) functioned as an advocacy organization on European issues. None of the organizations dealt with the critical aspects of risk management (e.g., a policy component dealing with best available practices, cost benefit analysis, lifecycle, product stewardship, etc.).
After several years of planning, the three organisations were merged. The Nickel Institute was founded, incorporating the activities of the three previous entities as well as including public policy issues such as risk management. NiPERA became the Institute’s independently incorporated science division.
Highlights of the past 40 years
Advent of REACH
In the 2000s the nickel industry faced a series of challenges related to a movement by the global regulatory community to increase standards of chemical safety. This included the comprehensive European risk assessment of nickel metal and several nickel compounds conducted under the European Union’s existing substances regulation, as well as various other regulatory initiatives. On both the human health and environmental sides, NiPERA played a leading role in drafting the risk assessment. The goal was to ensure that these regulatory actions were based on sound science and NiPERA stepped up to fill data gaps when needed. As the European chemical management regulation transitioned to the REACH program, NiPERA was again an instrumental and integral part of the Nickel Institute team enabling the nickel industry to maintain its science-based “license to produce and market” nickel in Europe and around the world.
Alloys are different
NiPERA first attended a workshop on alloys at Ispra, Italy in 2001 hosted by EURL ECVAM. At this meeting representatives from industry and academia agreed that from the point of view of risk assessment, alloys are materials with special properties that differ from those of simple mixtures of elements. The concept of using metal release data in surrogate biological fluids to refine the human health risk assessment of alloys was explored. It took the next 15 years for the metals industries to get the concept discussed in the EU regulatory arena and another few years to have a simple simulated gastric fluid protocol considered at the OECD. The story still continues with discussions on metal release data applicability to Classification and Labelling to be carried out in 2020 within the context of a CARACAL bioelution expert group and NiPERA continues to support this effort.
Mode of action for cancer
Since the 1980s NiPERA consistently funded research in vivo and in vitro to understand how nickel particles are taken up by cells and what effects they exert once they are inside these cells. Early studies looked at the relative carcinogenicity potency of various complex nickel oxides with varying ratios of Ni, Fe and Cu. The role that toxicity and inflammation play in the indirect genotoxicity by nickel substances was also explored including the role of nickel as a tumor promoter. The research culminated in studies of gene expression in vivo and studies with 3-dimensional lung models in vitro. A nickel bioavailability workshop and related publications provided a framework to integrate these elements and explain the different carcinogenicity potentials and potencies of various nickel substances. The research undertaken by NiPERA provided a solid basis for a threshold mode of action for cancer induction by nickel and this impacted the setting of occupational air standards.
Dose response assessment and calculation of human equivalent concentrations
Very early on NiPERA understood that workplace aerosols are different from animal experimental aerosols. NiPERA conducted several studies aimed at developing models to calculate human equivalent concentrations to animal aerosols taking chemical speciation into account. These efforts permitted us to compare and combine data from animal and human studies in dose-response assessments. The work has had a direct impact on the derivation of workplace and ambient air standards.
Bioavailability approaches for water
Nickel toxicity to aquatic organisms is influenced by the chemical constituents of freshwater, such as pH, water hardness, and dissolved organic carbon. These constituents vary greatly among freshwater systems across the globe. This means that assessing risks of nickel to aquatic ecosystems is most appropriately performed at a site- or region-specific scale. Within the Existing Substances Risk Assessment, NiPERA developed bioavailability models to support site-specific risk assessments. These approaches were later used in the REACH dossiers for nickel substances, as well as for establishing bioavailability-based environmental quality standards for Europe under the Water Framework Directive in 2013. Currently, these models are being used to develop similar approaches in Australia, Canada, and the USA.
Bioavailability approaches for soil
As for water, nickel toxicity to soil organisms also varies according to soil chemistry constituents, such as soil pH, clay content, and the amount of organic matter. NiPERA developed bioavailability approaches within the Nickel EU Risk Assessment that allow for the site-specific assessment of toxicity based on soil chemistry. These concepts were used in REACH, and were later applied in China, leading to the development of proposed bioavailability-based soil standards.
Sediment toxicity research program
Within the 2003-2008 EU Risk Assessment process, a scientific consensus was reached that all existing nickel toxicity data for the sediment compartment were flawed, and that new data and approaches were required. NiPERA organized a comprehensive research process that identified novel approaches for sediment spiking, produced a robust sediment ecotoxicity database, and developed bioavailability models to allow for site specific risk assessment. The outcome allowed for the successful registration of nickel compounds. The nickel sediment toxicity approach has been duplicated by other metals, and NiPERA has been invited to speak about this research by global regulatory and scientific groups.
The Ecotoxicology Technical Advisory Panel (ETAP), was established by NiPERA, the International Copper Association, and the International Lead Zinc Research Organization in 1995 to address cross-cutting environmental challenges facing the metals industries. ETAP allows industry scientists to raise issues with a panel of international academic scientists with expertise in metals ecotoxicology, environmental chemistry, and fate modeling. The ETAP process has yielded many accomplishments, including advances in bioavailability modeling for water, sediment, and soil; the development of approaches for determining appropriate environmental classifications of metals and sparingly soluble compounds; increased understanding of natural background and diffuse environmental metal sources; and, application of metal risk assessment to non-traditional areas like tropical, polar, and deep sea ecosystems. Currently, ETAP is sponsored by nine global metals research associations and metal producing organizations and continues to provide the metals industries with opportunities to jointly develop solutions to common environmental challenges.
ETAP provide the metals industries with opportunities to jointly develop solutions to common environmental challenges.
Tropical Environmental Risk Assessment Research Program
As nickel production shifted from traditional sulfidic deposits located predominantly in temperate climates to oxidic laterite deposits found in tropical regions, nickel producers became concerned about their abilities to assess environmental risks of nickel exposure to tropical ecosystems. In 2014, NiPERA initiated a research program to develop tools for tropical risk assessment. After identifying experts in this area, NiPERA’s research program developed tropical ecotoxicity databases for marine, freshwater, and sediment ecosystems, and identified bioavailability scenarios appropriate for tropical regions. A critical conclusion of this project is that no tropical organisms – not even corals – show greater sensitivity to nickel than temperate organisms. This allows for the pooling of tropical and temperate ecotoxicity data into an extremely robust database. The tropical program has contributed towards the establishment of bioavailability-based nickel water quality guidelines for Australia and is now being applied for similar purposes in New Caledonia.
NiPERA has consistently communicated its nickel-science over the past forty years, through many workshops on various research topics in addition to peer reviewed publications, factsheets and white papers. NiPERA staff also participate regularly at regulatory meetings in an expert capacity (OECD, CARACAL, ECHA, US EPA).
40 years of nickel science
The Nickel Producers Environmental Research Association (NiPERA) is an idea/concept in the nickel mining industry.
NiPERA is incorporated in the State of New York (USA) as a not-for-profit scientific organization on 28 July.
NiPERA is authorized to conduct affairs in the State of North Carolina (USA) as a not-for-profit organization on 10 May.
A seminal epidemiological study of around 80,000 workers in ten nickel production plants led by Sir Richard Doll is published.
ICNM (International Committee on Nickel Carcinogenesis in Man) 1990. Report of the International Committee on Nickel Carcinogenesis in Man. Scand J Work Environ Health 16(1) : 1-82
NiPERA launches a large ten year workplace industrial hygiene program. The program assesses occupational exposures and the performance of personal samplers, as well as developing a three-stage sampler for nickel. In addition, workplace nickel aerosols are characterized for particle size and chemical forms of nickel. The program establishes methods to quantitate dermal exposure and gathers data in various occupational settings. Analytical methods of speciation are applied to workplace and ambient air samples.
The first edition of the Safe Use of Nickel in the Workplace Guide is published by NiPERA and NiDI to provide guidance to nickel producing and using companies.
A significant epidemiological study update of high nickel alloy workers in the USA, commissioned by NiPERA is completed.
Arena VC, Sussman NB, Redmond CK, Costantino JP, Trauth JM. (1998). Using alternative comparison populations to assess occupation-related mortality risk. J Occup Environ Med.40:907-916.
Arena VC, Costantino JP, Sussman NB, Redmond CK. (1999). Issues and findings in the evaluation of occupational risk among women high nickel alloys workers. Am J. Ind Med.36(4):114-121.
The Ecotoxicology Technical Advisory Panel (ETAP) is formed by NiPERA and two other metals associations to address common environmental challenges facing the metals industries.
A compilation of workplace air and biomonitoring exposure and toxicology data (Criteria Document) is prepared by independent experts under NiPERA’s umbrella and submitted to the European Commission as a contribution to the setting of EU-wide occupational exposure limits for nickel.
NiPERA co-sponsored seminal research on the kinetics of oral absorption of nickel in human volunteers is published and later used by WHO for setting of drinking water guidelines for nickel.
Nielsen, G.D., Søderberg, U., Jørgensen, P.J., Templeton, D.M., Rasmussen, S.N., Andersen, K.E., Grandjean, P., 1999. Absorption and retention of nickel from drinking water in relation to food intake and nickel sensitivity. Toxicol. Appl. Pharmacol. 154, 67-75.
NiPERA establishes a Sample Repository to retain standardized samples of various nickel compounds used in NiPERA-sponsored testing around the world. The repository is a source of well-characterized samples for outside investigators working on nickel.
Seminal studies sponsored by NiPERA on the reproduction toxicity of nickel in rats are completed. These studies were used to set drinking water and oral reference values in several jurisdictions.
Springborn Laboratories, Inc. (SLI). An Oral (Gavage) 1-Generation Reproduction Study of Nickel Sulfate Hexahydrate in Rats; Study No. 3472.3; Springborn Laboratories, Inc.: Spencerville, OH, USA, 2000.
Springborn Laboratories, Inc. An Oral (Gavage) Two-Generation Reproduction Toxicity Study in Sprague-Dawley Rats with Nickel Sulfate Hexahydrate; Study No. 3472.4; Springborn Laboratories, Inc.: Spencerville, OH, USA, 2000.
A major reproductive study of female workers at the Monchegorsk nickel refinery in Russia concluded with the publication of several manuscripts. This study co-funded by the Ontario Workplace Safety and Insurance Board provided data on reproductive health risks for female workers associated with workplace nickel exposure.
Vaktskjold, A., Talykova, L., Chashchin, V., Nieboer, E., Thomassen, Y., Odland, J., 2006. Genital malformations in newborns of female nickel-refinery workers. Scand. J. Work Environ. Health 32 (1), 41-50.
Vaktskjold, A., Talykova, L., Chashchin, V., Odland, J., Nieboer, E., 2008. Spontaneous abortions among nickel-exposed female refinery workers. Int. J. Environ. Health
The Transformation/Dissolution Protocol (T/D P) is adopted by UN Globally Harmonized System. The T/D P is an approach that measures the dissolution of metals at standard loadings and uses the dissolution rate as the means to apply environmental classifications to metals and sparingly soluble metal compounds. NiPERA collaborated with other metal associations and testing laboratories in Europe and Canada in the development of this important protocol.
The European Union conducts the Existing Substances risk assessment of five priority nickel substances. For the Human Health section, NiPERA provides toxicological data and fills data gaps. For the Environment section, NiPERA partners closely with the Danish Rapporteur to introduce novel environmental risk assessment concepts that have had enormous global influence.
On 1 January, NiPERA Inc. and Nickel Development Institute merge and NiPERA becomes an independently incorporated division of the Nickel Institute.
Two key cancer bioassays in rats are completed and published: the oral carcinogenicity study of nickel sulfate hexahydrate (Heim et al 2007) and an inhalation carcinogenicity study with nickel metal powder (Oller et al., 2008). They both fulfill important data gaps to inform hazard identification and classification.
Heim K, Bates H, Rush R, Oller AR, 2007 Oral Carcinogenicity Study with Nickel Sulfate Hexahydrate in Fischer 344 rats. Toxicol. Appl. Pharmacol., 224: 126–137
Oller AR, Kirkpatrick DT, Radovsky A, Bates HK, 2008. Inhalation carcinogenicity study with nickel metal powder in Wistar rats. Toxicol. Appl. Pharmacol.. 233: 262-275
REACH registration dossiers for 11 nickel substances are prepared. The Nickel Institute acts as the Secretariat for the Nickel REACH Consortia.
A research program in conjunction with the Danish EPA is launched to fill an obligation for REACH to understand the effects of nickel to the sediment compartment. The outcome is the most robust sediment toxicity approach for any chemical substance.
Schlekat CE, Garman ER, Vangheluwe MLU, Burton GA, Jr. 2016. Development of a bioavailability-based risk assessment approach for Ni in sediments. Integrated Environmental Assessment and Management. 12: 735-746.
NiPERA proposes an approach which enables a bioavailability-based nickel Environmental Quality Standard (EQS) to be adopted for the first time in Europe. Compliance with the standard which is based on strong science enables Nickel Institute Members and downstream users of nickel to have confidence that their operations are not impacting the environment.
Merrington G, Peters A, Schlekat C. 2016. Accounting for metal bioavailability in assessing water quality: A step change? Environ Toxicol Chem 35: 257-265
Tropical ecosystems will serve as the next source of nickel for the global economy. NiPERA establishes a research program which develops tools for performing refined environmental risk assessments of nickel in these sensitive areas.
A pivotal NiPERA study on mechanisms of nickel toxicity to aquatic organisms is published. Information on the mechanistic basis of nickel toxicity is critical to the use of bioavailability models like the Biotic Ligand Model.
Brix KV, Schlekat CE, Garman E. 2016. The mechanisms of nickel toxicity in aquatic environments: An Adverse Outcome Pathway (AOP) analysis. Environ Toxicol Chem 36: 1128-1137.
The organization officially changes its name from Nickel Producers Environmental Research Association, Inc. to NiPERA Inc.
NiPERA helps organize and chair a SETAC Technical Workshop on metals bioavailability modeling. This results in six publications and serves as the basis for global regulatory agencies to set bioavailability-based standards for metals like nickel.
Schlekat CE, Stubblefield WS, Gallagher K. 2020. State of the Science on Metals Bioavailability Modeling: Introduction to the outcome of a SETAC Technical Workshop. Environ Toxicol Chem 39: 42-47
Garman, E.R., Meyer, J.S., Bergeron, C.M., Blewett, T.A., Clements, W.H., Elias, M.C., Farley, K.J., Gissi, F. and Ryan, A.C. (2020), Validation of Bioavailability‐Based Toxicity Models for Metals. Environ Toxicol Chem, 39: 101-117.
Brix, K.V., DeForest, D.K., Tear, L., Peijnenburg, W., Peters, A., Middleton, E.T. and Erickson, R. (2020), Development of Empirical Bioavailability Models for Metals. Environ Toxicol Chem, 39: 85-100.
In Europe ECHA’s risk assessment committee issued an opinion on the occupational exposure levels for nickel compounds. This paves the way for the setting of harmonized occupational exposure levels in Europe that had been in discussion since the 1990s. In reaching their opinion, the committee included data from studies funded by NiPERA over the last 30 years.
NiPERA hosts a tropical risk assessment workshop to communicate information gathered through the tropical risk assessment research program. It reaches the scientific and regulatory communities of Southeast Asia and Melanesia, including Indonesia and New Caledonia. The event catalyzes interest in developing Ni EQSs that are specific for tropical regions, and our work in New Caledonia is an example of this.
NiPERA’s team of toxicologists published a concise review of nickel toxicology in the journal of Inorganics. This review is unique in that it combines human health effects with environmental effects to ecosystems.
Buxton S, Garman E, Heim KE, Lyons-Darden T, Schlekat CE, Taylor MD, Oller AR. 2019. Concise review of nickel human health toxicology and ecotoxicology. Inorganics 7(7): 89.