IRIS Toxicological Review of Cobalt and Compounds (Inhalation)
Toxicological Review IRIS Assessment Coblt
2022-11-17 2022-12-16
EPA-HQ-ORD-2022-0833-0002 EPA-HQ-ORD-2022-0833-0006
05:00:00 05:00:00
https://api.regulations.gov/v4/comments/EPA-HQ-ORD-2022-0833-0002 https://api.regulations.gov/v4/comments/EPA-HQ-ORD-2022-0833-0006
Anonymous Anonymous
Anonymous Anonymous
1) Section 2.2. Scoping Summary indicates that all cobalt containing substances are considered for this assessment with the exception of radioactive cobalt (60Co) and vitamin B12. This suggests that all cobalt containing substances including alloys with varying physical properties are within the scope of this assessment. The assessment appears to be relying largely on prior assessments in addition to a literature review of newer studies published 2019-2021. Key prior reviews contained language that specifically excluded cobalt alloys from their evaluation including NTP (2016) and OEHHA (2020). Therefore, relying exclusively on the references  of these prior reviews to evaluate mechanism and ADME of all cobalt containing substances inclduing diverse alloys might have flaws. As a single example, one study on the disposition of inhaled CoCr grinding dust from dental alloys was not referenced in OEHHA (2020) and NTP (2016) [Brune, D., Kjserheim, A., Paulsen, G.  Beltesbrekke, H.: Pulmooar,  Deposition following inhalation of chromium-cobalt grinding dust in rats and distribution in other tissues. Scand, J. Dent. Res. 1980: 88: 543^551].  Please consider whether a new literature search for additional studies related to the disposition and toxicity for cobalt containing alloys may be appropriate.2) Section 3,2 Specific Aims discusses the possibility of developing separate inhlation unit risk factors for water soluble and insoluble compounds as was done in OEHHA (2020). The Assessment Plan under Section 2.4 Key Scientific Issues also discusses the importance of the dissolution of low water soluble or insoluble compounds in biological fluids inclduing the lower pH of the lysosome. Some cobalt alloys are highly corrosion resistant and are not only water insoluble but may also have very low solubility in lysosomal fluids. Such particles may have greatly different ADME properties and toxicity compared with the cobalt metal powder used in the NTP study. A single inhalation unit risk factor for all water insoluble substances may not be scientifically justifiable. I would like to urge EPA IRIS to consider the rate of dissolution as proposed in section 2.4 and the physical clearance from the lung of different alloy particulates in the Assessment rather than assuming that all cobalt containing water insoluble substances are the same with a single dose-response assessment. A separate unit risk factor for cobalt alloy that have low solubility in lysosomal fluid, if supportable, would be a benefit to the regulatory community since there are facilities which release alloy grinding dust into the environment. Alternatively, limitations on the application of the URFs developed for different water insoluble particulates should be included in the Assessment. The Cobalt Institute is submitting detailed comments on the EPA IRIS assessment plan and protocol for Co and Co compounds in the two attachments to this submission (i.e. CI response into IRIS PC 2022Dec13 and Stantec ChemRisk Cobalt Comments IRIS). We have provided the Executive Summary of the CI response below.Executive SummaryCobalt and cobalt compounds were nominated by the EPAs Office of Air and Radiation (OAR), in June 2022 for a cancer assessment under the US EPA IRIS Program due to potential carcinogenic risks arising from emissions to air of cobalt compounds during industrial processes. The Cobalt Institute (CI) is submitting comments in December 2022, relating to the consultation on the IRIS Assessment Plan (IAP) and protocol for Co and Co compounds.  The CI recently published a series of papers containing data on the cobalt mode-of-action (MOA) relating to longer-term inhalation toxicity and carcinogenicity of cobalt and cobalt compounds. In these publications, the CI has performed a tiered, mode-of-action based read-across approach, detailing the distinct differences in the release of the Co ion in artificial lung fluids, upregulation of in vitro biomarkers for hypoxia, inflammation, oxidative stress and acute toxicity/persistent inflammatory responses and sub-acute toxicity, between the reactive Co substances (represented by Co metal and Co sulfate) and the poorly reactive / poorly soluble Co substances (represented by tricobalt tetraoxide). Based on this and other extensive datasets, Co metal is not considered as part of the poorly soluble group of substances. In contrast, tricobalt tetraoxide is poorly soluble in all lung fluids and high quality, mode-of-action data indicates a lower potency and potential alternative cancer MOA for poorly soluble cobalt substances. The existence of different groups of cobalt substances, and the grouping of Co metal with the reactive substances, is supported by the recent IARC review of Co and Co compounds. In addition, mutagenic responses (i.e. direct genotoxicity) have not been detected in guideline-compliant studies with any cobalt substance, including the substances that were positive for cancer by inhalation exposure in rodent studies.The CI proposes that the EPA uses a weight-of-evidence approach to assess the dose-response for reactive, bioavailable cobalt substances taking into account MOA, animal and epidemiological (workplace) data. A multi-year testing program has been provisionally approved and will inform on the MOA, dose-response and tissue deposition of poorly soluble/ poorly reactive Co substances and in vivo site of contact genotoxicity and inflammatory responses induced by reactive Co substances. Combined, all evidence on the carcinogenicity of cobalt can be reconciled into one mode-of-action paradigm and into one continuous exposure response with a good estimation of a threshold in the dose response curve. The essential biological role of cobalt and its extensive mechanistic, genotoxicity and toxicity data fit the overall profile of a carcinogen with a threshold mode-of-action and this is consistent with the available epidemiological data. In contrast, current linear approaches based solely on animal data yield a predicted excess cancer risk that cannot be reconciled with the lack of excess cancer cases observed in the epidemiology studies. In both NTP cancer bioassays (cobalt sulfate and cobalt metal powder), adrenal pheochromocytoma were observed. These tumors are a well-known secondary response to respiratory distress of any origin (not just lung cancer) and should not be interpreted as independent cobalt-related tumors. Further systemic tumors were only seen in one sex of rats (not in mice) in the cobalt metal powder study. The rat strain and colony used in this inhalation study does not have a historical control database against which these tumors can be compared, making the interpretation of these findings extremely difficult. Further, there was no exposure-response in any of these findings. The conclusion of independence of these tumors appears implausible. The CI promotes the responsible and sustainable production and use of cobalt in all its forms and applications. The Institute aims to protect and grow the market for cobalt and compounds by promoting a proportionate regulatory environment. We welcome any additional requests or clarifications from the US EPA regarding the current submission and would appreciate the opportunity for cooperation and communication to lead to the appropriate risk management measures and limit values applied to cobalt and cobalt substances. 