Reapplication of the Type IV Hypersensitivity Quantitative Risk Assessment to Assess Ingredients Used on Canines

Abstract

A quantitative risk assessment (QRA) framework to assess the risk for the induction of human skin sensitization from exposure to contact allergens has been successfully developed and applied. So far, the QRA has not been applied in a canine risk assessment for establishing concentration limits of ingredients with Type IV hypersensitivity potential. Outlining this risk assessment is critical, as shampoos are known to cause allergic contact dermatitis (ACD) in canines. Additionally, humans have developed ACD after washing their dogs with dog shampoo. To address this gap, we conducted a thorough literature review on canine Type IV hypersensitivity and identified potential differences which might demand an adaptation of the QRA. We summarize data from the literature demonstrating that all four key events (KE) in the skin sensitization adverse outcome pathway (AOP) are present in dogs as they are in humans, guinea pigs, and mice. The hazard potential of sensitizers for canines is compared with the established sensitization QRA framework for humans. The limited collective evidence suggests that dogs are not more susceptible to sensitizers than humans; therefore, safety-defined concentration limits from Type IV hypersensitivity risk assessments for humans can be re-applied to canines so long as their unique exposure considerations are factored in. Using the principles in this review, one can evaluate chemical sensitizers to support the safe development of new topical formulations for canines. The result of applying our current best approaches for assessing ACD to canine products should protect both the pet and the owners.

Keywords: Allergic Contact Dermatitis; Animal Science; Canine/Dog; Quantitative Risk Assessment; Skin Sensitization.

FIGURE 1

Overview of the skin sensitization quantitative risk assessment process. In step 1, a WoE NESIL is chosen from appropriate in vitro, in vivo, and clinical data. The NESIL can be treated as a canine NOAEL for Type IV hypersensitivity assessments. In step 2, the AEL is calculated by taking the NESIL and dividing it by the SAFs depending on the product category. In step 3, the AEL is divided by the CEL (actual consumer exposure) to calculate the MOS. If this MOS is ≥1, no induction of sensitization is expected, and the formula is supportable for the proposed consumer product. NESIL, no expected sensitization induction level; NOAEL, no observed adverse effect level.

FIGURE 2

Evidence to support that key events of Type IV hypersensitivity reactions are conserved between humans and dogs. (A) KEGG signalling pathways mapped using human ortholog predictions which are manually drawn demonstrate that pathways involved in Th1 and Th2 cell differentiation between humans and canines are 100% shared. Link to view human Th1 and Th2 cell differentiation pathway: https://www.kegg.jp/pathway/hsa04658. Link to view canine Th1 and Th2 cell differentiation pathway: https://www.kegg.jp/pathway/cfa04658+403856. (B) AI‐generated figures summarize that the four Type IV hypersensitivity key events are present in dogs. The corresponding paragraphs offer more detail and have references. Chat‐GPT4o (ImagePG). Reference: OpenAI. (2024). ChatGPT 4o (May 2024 version) [Large Language model]. https://chat.openai.com/chat.

FIGURE 3

Summary of rationale to re‐apply human protective hazard data to dogs and outline of canine Type IV hypersensitivity risk assessment framework. (A) WoE rationale to treat human NESILs as canine Type IV hypersensitivity NOAELs. (B) Canine Type IV hypersensitivity risk assessment framework and graphical exposure examples. Images are AI‐generated by P&G's internal version of Chat‐GPT4o (ImagePG). Notice: The AI‐generated skin and hair magnification images may not be biologically accurate and are only intended to show the increased residue that would remain on a dog's skin from wiping off or leaving on products. NESIL, no expected sensitization induction level; NOAEL, no observed adverse effect level). Reference: OpenAI. (2024). ChatGPT 4o (May 2024 version) [Large Language model]. https://chat.openai.com/chat.