Cross-reactivity between thiuram disulfides and dithiocarbamates. A study of TETD and ZDEC using mouse models

Abstract

Background: Rubber accelerators are used in the vulcanization of rubber. However, rubber accelerators for example tetraethylthiuram disulfide (TETD) and zinc diethyldithiocarbamate (ZDEC) may cause contact allergy. Concomitant reactions between ZDEC and TETD have been observed in patients which could be explained by co- or cross-reactivity.

Objectives: To investigate cross-reactivity between TETD and ZDEC and vice versa.

Methods: Groups of mice were sensitized with TETD or ZDEC based on reported EC3-values. Proliferation of lymphocytes were measured on day 5. To test cross-reactivity, mice were sensitized and challenged 3 weeks later with TETD or ZDEC. The inflammatory response was measured by changes in ear thickness and the proliferative response in CD4⁺ and CD8⁺ T cells in the submandibular and cervical draining lymph nodes.

Results: Sensitization of mice with doses of ZDEC 3%, TETD 5.6% or TETD 16.2% induced significant increased ear thickness and proliferation of CD4⁺ and CD8⁺ T cells. Challenge with ZDEC or TETD in these groups induced significant increased ear thickness. Challenge with ZDEC in mice sensitized to TETD 5.6% or TETD 16.2% induced significant increased proliferation of CD4⁺ and CD8⁺ T cells.

Conclusions: We show cross-reactivity between TETD and ZDEC. Patients sensitized to TETD or ZDEC should avoid exposure to both ZDEC and TETD.

Keywords: TETD; ZDEC; allergic contact dermatitis; contact allergy; contact dermatitis; dermatitis; dithiocarbamates; immunology; rubber accelerators; thiurams.

FIGURE 1

Chemical formula of zinc diethyldithiocarbamate (ZDEC) and tetraethylthiuram disulfide (TETD). The molecular weight of TETD is 296.5 g/mol and the molecular weight of ZDEC is 361.91 g/mol. N, nitrogen; S, sulfur; ZN, zinc.

FIGURE 2

The responses to zinc diethyldithiocarbamate (ZDEC) and tetraethylthiuram disulfide (TETD) during sensitization. (A) Experimental setup: mice were exposed to olive oil:acetone (OOA), 0.3% ZDEC, 1% ZDEC, 3% ZDEC, 1.8% TETD, 5.4% TETD or 16.2% TETD on day (D) 0–2 for sensitization and sacrificed on D 5. Ear thickness was measured before first exposure at D 0 and before sacrifice on D 5. Submandibular and cervical draining lymph nodes (dLN) were isolated for flow cytometry on D 5. (B–D) Mice were exposed to OOA/control (white) ZDEC (blue) and TETD (orange) (n = 8). Each dot represents data from one mouse, bars represent the mean and error bars represent the standard deviation (SD) for each group. (B) Percental change in ear thickness at D 5 when normalised to mean ear thickness at D 0. (C–D) Flow cytometry data; (C) Ki67⁺CD4⁺TCRβ⁺ T cells and (D) Ki67⁺CD8α⁺TCRβ⁺ T cells. Statistical comparisons to control group by one‐way ANOVA. Statistical significance levels; *p ≤ 0.05, **p ≤ 0.01, ***p ≤ 0.001, ****p ≤ 0.0001.

FIGURE 3

Cross‐reactive challenge responses between zinc diethyldithiocarbamate (ZDEC) and tetraethylthiuram disulfide (TETD). (A) Experimental setup: mice were exposed to olive oil:acetone (OOA), 0.3% ZDEC, 1% ZDEC, 3% ZDEC, 1.8% TETD, 5.4% TETD or 16.2% TETD on day (D) 0–2 for sensitization (Sen.) and challenged (Chal.) on D 21 to either OOA, 1% ZDEC or 5.4% TETD. Mice were sacrificed 24 h later (D 22). Ear thickness was measured at D 21 before re‐exposure and 24 h later before sacrifice (D 22) and submandibular and cervical draining lymph nodes (dLN) were isolated for flow cytometry (D 22). (B–G) Mice were exposed to OOA/control (white), ZDEC (blue), TETD (orange) and cross‐reactions between ZDEC and TETD (striped). Each dot represents data from one mouse, bars represent the mean and error bars represent the standard deviation (SD) (n = 8). (B–C) Percental change in ear thickness at D 22 when normalised to mean ear thickness at D 21. (B) Ear thickness of mice challenged with 1% ZDEC. (C) Ear thickness of mice challenged 5.4% TETD. (D–G) Flow cytometry data (D) Ki67⁺CD4⁺TCRβ⁺ T cells in mice challenged with 1% ZDEC. (E) Ki67⁺CD4⁺TCRβ⁺ T cells in mice challenged with 5.4% TETD. (F) Ki67⁺CD8α⁺TCRβ⁺ T cells in mice challenged with 1% ZDEC. (G) Ki67⁺CD8α⁺TCRβ⁺ T cells in mice challenged with 5.4% TETD. Statistical comparisons to control group by one‐way ANOVA. Statistical significance levels; *p ≤ 0.05, **p ≤ 0.01, ***p ≤ 0.001, ****p ≤ 0.0001.