Current research initiatives on human and environmental health effects of nickel Adriana R. Oller, PhD, DABT INSG Meeting Outline About NiPERA Strategy to read across human health toxicities for Ni compounds Example: oral route Aquatic Ni toxicity and setting of Environmental Quality Standards (EQS) Conclusions 2
ABOUT NIPERA 3 Producers Environmental Research Association, Inc NiPERA Inc. is a not-for-profit association and the science branch of the global Institute The Institute represents the interests of 25 companies which together produce more than 75% of the world s annual nickel output Mission: Promote and support the use of nickel in appropriate applications 4
Producers Environmental Research Association, Inc NiPERA Conducts research on environmental and human health effects of nickel and its chemicals in order to: Assure the safe production and use of nickel in appropriate applications Support appropriate classifications for nickel containing substances Promote the setting of global reference values (EQS, OELs) that are based on science, sufficiently protective of human health and the environment and not overly precautionary 5 Risk Assessment E.g., classification for reproductive toxicity E.g., EQSs 6
STRATEGY TO READ ACROSS HUMAN HEALTH TOXICITIES FOR NI COMPOUNDS 7 Metal Substances Registered in 2010 Source: REACH Metals Gateway (www.reach-gateway.eu) 8
2010 REACH Registration of Ni Metal and 10 Ni Compounds Information on 14 health endpoints for 11 substances had to be filled in! Toxicity Endpoint for GHS Classification Sulphate Chloride Nitrate Oxide (Black & Green) Hydroxycarbonate Dihydr oxide Sulphamate Acetate Subsulfide Sulphide Metal Dermal Irritation/Skin Corrosion (GHS) Eye Irritation Dermal Sensitization Acute Oral Toxicity STOT-SE (oral) Acute Inhalation Toxicity STOT-SE (inhalation) Acute Dermal Toxicity STOT-SE (dermal) RE (oral) RE (dermal) RE (inhalation) Reproductive Toxicity Respiratory Sensitization 9 REACH Registration of Ni Metal and 10 Ni Compounds Fortunately, we had fairly complete datasets for 4 substances (Reference Substances) Toxicity Endpoint for GHS Classification Sulphate Chloride Nitrate Oxide (Black & Green) Hydroxycarbonate Dihydr oxide Sulphamate Acetate Subsulfide Sulphide Dermal Irritation/Skin Corrosion (GHS) What do we do about the data-poor substances? Metal Eye Irritation Dermal Sensitization Acute Oral Toxicity STOT-SE (oral) Acute Inhalation Toxicity STOT-SE (inhalation) Acute Dermal Toxicity STOT-SE (dermal) RE (oral) RE (dermal) RE (inhalation) Reproductive Toxicity Respiratory Sensitization 10
Read-Across It is the process by which an assessment/prediction of hazard for a data-poor substance is made It uses existing toxicity information from well-characterized substances and some measure of the likelihood that the datapoor substance will behave in the same manner as the reference substance i.e., have similar physical-chemical environmental fate properties, similar toxicokinetics Data-rich substance = reference substance Data-poor substance = substance being studied 11 REACH Registration of Ni Metal and 10 Ni Compounds How do we apply read across to data-poor substances? Toxicity Endpoint for GHS Classification Sulphate Chloride Nitrate Oxide (Black & Green) Hydroxycarbonate Dihydr oxide Sulphamate Acetate Subsulfide Sulphide Metal Dermal Irritation/Skin Corrosion (GHS) Eye Irritation Dermal Sensitization? Acute Oral Toxicity STOT-SE (oral) Read across Acute Inhalation Toxicity STOT-SE (inhalation) Acute Dermal Toxicity STOT-SE (dermal) RE (oral) RE (dermal) RE (inhalation) Reproductive Toxicity Respiratory Sensitization 12
Routes of Exposure and Toxicities ORAL Ni Compound Absorption Bioavailable Ni (II) Ion Systemic Toxic effects effects 13 Routes of Exposure and Toxicities DERMAL Bioavailable Ni (II) Ion on skin Ni Compound Example Dermatitis Irritation 14
Routes of Exposure and Toxicities Bioavailable Ni (II) Ion at Extra- or Intra-cellular Respiratory Sites INHALATION ExampleLocal Chronic effects Respiratory toxicity Respiratory Carcinogenicity i it -containing aerosol 15 Example: Bioaccessibility-based read across and Oral Route ORAL Compound Absorption Bioavailable Ni (II) Ion Gastric fluid Toxic Effects Relative Bioaccessible Ni (II) Ion 16
Example: Bioaccessibility-based read across and Oral Route and Oral Route ORAL Compound Absorption Relative Bioavailable Ni (II) Ion Gastric fluid Relative Bioaccessible Ni (II) Ion 17 Example: Bioaccessibility-based read across and Oral Route Bioa accessibility in gastric fluid 100 90 80 70 60 50 40 30 20 10 0 Step 1: generate bioaccessibility data More Ni release Less Ni release In nverse of in vivo toxicity Step 2: verify with animal data Less toxic More toxic In vitro bioaccessibility 18
Example: Bioaccessibility-based read across and Oral Route Bioa accessibility in gastric fluid 100 90 80 70 60 50 40 30 20 10 0 Step 1: generate bioaccessibility data More Ni release Less Ni release In nverse of in vivo toxicity Step 2: verify with animal data Less toxic In vitro bioaccessibility More toxic Step 4: read across classifications Step 3: group compounds and identify best references 19 Example: Bioaccessibility-based read across and Oral Route Step 4: read-across classifications Toxicity Classification No Classification 20
EU Classifications of Ni & Ni Compounds Of 66 combinations of substances x health endpoints for which some classification exist, bioleution-based read across with in vivo verification resulted in 17 changes Toxicity Endpoint for GHS Classification Sulphate Chloride Nitrate Oxide (Black & Green) Hydroxycarbonate Dihydroxide Sulphamate Acetate Subsulfide Sulphide Dermal Irritation/Skin Corrosion (GHS) none none none none none Eye Irritation None none none None None none none none none Dermal Sensitization Acute Oral Toxicity none none None Acute Inhalation Toxicity none RE (inhalation) Carcinogenicity Reproductive Toxicity none none none Respiratory Sensitization none none none 21 Regulatory Acceptance of Read Across The full validation of the read across approach for oral toxicity of nickel compounds has been published Full validation for other routes is ongoing Metal commodity associations have been working together to gain recognition of bioaccesibility-based read-across methodologies by ECHA Workshop with ECHA and Member States representatives- Helsinki Read across approaches presented by different metal commodities Bioaccessibility-based read across accepted as a plausible approach for classification and DNEL derivation, with sufficient justification Important consideration as we face the classification of alloys in 2015 Bioaccessibility-based effective concentration of metals in alloys! 22
Aquatic Ni toxicity: why is bioavailability normalization necessary? Ni toxicity to a snail EC50 90 Low 80 70 60 50 40 30 20 10 High 0 0 1 2 3 4 5 6 7 Different Sites Toxicity Ni 2+ toxicity to aquatic organisms varies as a function of water chemistry Ni toxicity is influenced by ph, hardness (Ca 2+, Mg 2+ ), and dissolved organic carbon (DOC) Dissolved Ni alone is not a good predictor of toxicity! High ph (low H + ), low DOC Low ph (high H + ), high DOC 23 Aquatic Ni toxicity: why is bioavailability normalization necessary? >17µgNi/L 1.7 Water chemistry varies greatly across surface waters Ni, but also ph, hardness and dissolved organic carbon EU original approach for Environmental Quality Standards (EQSs): Select a single Reasonable Worst Case value to protect most sensitive waters 2004 proposal: 1.7 µg Ni/L 24
Aquatic Ni Toxicity: the Biotic Ligand Model (BLM) provides a tool for bioavailability normalization of Ni Chronic Biotic Ligand Models (BLM) Accounts for: Complexation of Ni 2+ by dissolved organic carbon Competition with Ca 2+, Mg 2+, and H + Available for several species Invertebrates Fish Algae Extrapolated to 31 species of algae, vascular plants, invertebrates, fish, and amphibians redicted toxicity Pr predicted 17d-LC50 (µg Ni/L) 10000 1000 100 rainbow trout ph set Mg set Ca set Natural 100 1000 10000 observed 17d-LC50 (µg Ni/L) Validated for >95% of water chemistry occurring in EU ph: 6.5 8.7 Ca content: 2 to 88 mg Ca/L Observed toxicity 25 Aquatic Ni Toxicity: Limitations to BLMs- Ecological boundaries Currently, Ni BLMs have been validated for European and North American surface waters The European Commission proposed their use in the Ni EQS 2012 proposal: EQS bioavailable = 4 µg Ni/L Concerns have been raised about the validity of these BLMs in other regions China Russia Canada Australia Ni geochemistry and physiology should be universal, and so should Ni toxicity
Current research initiatives on human and environmental health effects of nickel Conclusions NiPERA ( Institute) continues its mission to fill in existing datagaps and generate information about human and environmental health effects of nickel Importantly, we also develop the tools to bring the new information into the regulatory frameworks in order to promote the setting of standards and regulations that are sufficiently protective while being achievable by best industrial practices 27 Current research initiatives on human and environmental health effects of nickel THANK YOU FOR YOUR ATTENTION! Email address: aoller@nipera.org 28