IRIS Public Science Meeting (Jan 2023)

Meeting Details

The IRIS Program convene IRIS Public Science Meetings to encourage the scientific community and the public to participate in discussions on IRIS draft assessment materials.

At this meeting, the IRIS Program invited the public to the discussion on the key science issues identified in the following document:

• IRIS Assessment Plan and Protocol for Assessing Cancer Risk from Inhalation Exposure to Cobalt and Cobalt Compounds (Scoping and Problem Formulation Materials) 

Dates

• The meeting will be held on January 11, 2023 .
• Registration opened on December 13, 2022.
  •  Meeting Registration link

Meeting Materials

The final agenda is posted below: 

• IRIS Webinar Meeting Final Agenda  Jan 2023 (PDF) (2 pp, 167 KB)
• IRIS Public Science Meeting EPA Presentation Slides, Jan 2023 (PDF) (68 pp, 5MB)  

Cobalt Key Science Topics and Materials

Cobalt Assessment Manager: Dr. Ravi Subramaniam

• IRIS Assessment Plan and Protocol for Assessing Cancer Risk from Inhalation Exposure to Cobalt and Cobalt Compounds (Scoping and Problem Formulation Materials)
• Primary Literature Search References Sorted by Author (Cobalt and Cobalt Compounds) (dynamic literature link - generated by HERO)

Key Science Topics

What is an IRIS Assessment Plan? An IRIS Assessment Plan (IAP) communicates to the public the plan for assessing each individual chemical and includes summary information on the IRIS Program’s scoping and initial problem formulation; objectives and specific aims for the assessment; the PECO (Populations, Exposures, Comparators, and Outcomes) criteria that outlines the evidence considered most pertinent to the assessment; and identification of key areas of scientific complexity.

The IRIS Program is seeking a discussion with the public aimed at improving or clarifying the IAP. Below are questions to facilitate the discussion of these science topic:

• Are the assessment objectives and specific aims articulated clearly?
• Does the background information and context that is provided support the objectives for the assessment presented in the plan? 
• Does the proposed PECO (Populations, Exposures, Comparators, Outcomes) framework identify the most pertinent evidence to address the stated needs of the Agency programs and regions?

Science Topics

Topic 1. Association between lung and adrenal tumor formation 

The IRIS program is seeking discussion on a plausible association between lung and adrenal gland tumors associated with exposure to cobalt and cobalt compounds. Background information is provided below.

An analysis of the results of NTP inhalation exposure studies in rats found an apparent association between the occurrence of pulmonary non-neoplastic lesions and the development of pheochromocytomas. This plausible association has been attributed to the adrenal response arising from systemic hypoxemia due to the reduced gas exchange induced by the lung lesions and the accompanying fibrosis and chronic inflammation. Assessment of the dependence of the tumor types impacts upon the method used to estimate composite cancer risk. A combined tumor analysis may not be appropriate if tumors do not form independently.

Topic 2. Cellular Uptake and Tissue Disposition

The IRIS program is seeking discussion on cellular uptake and tissue disposition associated with exposure to cobalt and cobalt compounds. Background information is provided below.

Although cobalt bioavailability and its influence on carcinogenicity are not fully understood, it is known that cellular uptake of free cobalt ion and particles occur via different processes; differences between uptake and distribution of water-soluble and water-insoluble cobalt compounds could lead to differences in pharmacodynamics. Mechanistic information regarding cellular uptake and tissue deposition can inform dosimetric adjustments and modeling approaches.

Topic 3. Cobalt Particle Toxicity

The IRIS program is seeking discussion on particle toxicity associated with exposure to cobalt and cobalt compounds. Background information is provided below.

In addition to potential differences in particle ion uptake and distribution that might influence tissue dosimetry, cobalt is a redox-active transition metal. Cobalt particles may have a greater effect than ions in catalyzing production of reactive oxygen species (ROS). How cobalt ions are released in vivo also differs between water-soluble and water-insoluble cobalt compounds. Updating the mechanistic evidence concerning whether cobalt particles may elicit direct toxicity contributing to carcinogenesis will help inform the choice of the particle lung dose metric used for rodent-to-human extrapolation and dose-response.

Topic 4. Proposed MOA of cobalt carcinogenicity

The IRIS program is seeking discussion on the potential MOA of cobalt and cobalt compounds. Background information is provided below.

There is evidence that cobalt-induced neoplastic development likely involves pathways of genotoxicity, oxidative stress (and generation/scavenging of ROS), and stabilization of hypoxia-inducible factor 1α. Other evidence suggests that cobalt genotoxicity involves primarily clastogenic effects, as well as direct and indirect DNA damage and inhibition of DNA repair. Updating the current evidence in the proposed cobalt cancer MOA, including capturing any new evidence of mechanistic responses beyond those previously described, will help inform the dose-response analyses, pharmacokinetic evaluations, and animal-to-human extrapolation methodologies.

Substances that can release cobalt ions in vivo, both water soluble and insoluble, likely define the domain of applicability for this assessment.