Patch Test Positivity to Palladium: A 5-Year Retrospective Study in Triveneto Region, Italy.

BACKGROUND: The use of palladium (Pd) is increasing in metal objects after the banning of nickel in items in prolonged contact with the skin. The properties of Pd make this metal useful in various industrial fields. OBJECTIVE: The aim of the study was to evaluate the prevalence of Pd sensitization in patients who underwent patch tests for suspected allergic contact dermatitis in the Triveneto region from 2013 to 2018. METHODS: A total of 4816 patients with symptoms and/or signs of suspected contact allergic dermatitis were patch tested. Individual characteristics were assessed using a standardized questionnaire. RESULTS: The overall prevalence of Pd sensitization was 7.6% and 10.8% using PdCl2 1% or 2% petrolatum, respectively, with a higher prevalence in women (odds ratio, 2.6; 95% confidence interval, 1.9-3.7) and in 26- to 55-year-old patients. Monosensitization occurred in 1%-1.5% of the patients tested. Health care workers and technicians were more sensitized to Pd than clerks, but the data did not reach statistical significance. CONCLUSIONS: Palladium sensitization was high, but it was mainly associated with nickel sensitization. A possible occupational role was found for workers with potential contact with Pd-containing objects, but more data are needed to reach statistical significance.

Patch test-relevant concentrations of metal salts cause localized cytotoxicity, including apoptosis, in skin ex vivo.

BACKGROUND: Metal alloys containing contact sensitizers (nickel, palladium, titanium) are extensively used in medical devices, in particular dentistry and orthopaedic surgery. The skin patch test is used to test for metal allergy. OBJECTIVE: To determine whether metal salts, when applied to freshly excised skin at patch test-relevant concentrations and using a method which mimics skin patch testing, cause in changes in the epidermis and dermis. METHODS: Tissue histology, apoptosis, metabolic activity, and inflammatory cytokine release were determined for two nickel salts, two palladium salts, and four titanium salts. RESULTS: Patch test-relevant concentrations of all metal salts caused localized cytotoxicity. This was observed as epidermis separation at the basement membrane zone, formation of vacuoles, apoptotic nuclei, decreased metabolic activity, and (pro)inflammatory cytokine release. Nickel(II) sulfate hexahydrate, nickel(II) chloride hexahydrate, titanium(IV) bis(ammonium lactato)dihydroxide, and calcium titanate were highly cytotoxic. Palladium(II) chloride, sodium tetrachloropalladate(II), titanium(IV) isopropoxide, and titanium(IV) dioxide showed mild cytotoxicity. CONCLUSION: The patch test in itself may be damaging to the skin of the patient being tested. These results need further verification with biopsies obtained during clinical patch testing. The future challenge is to remain above the elicitation threshold at noncytotoxic metal concentrations.

Thyroid Stem Cells But Not Differentiated Thyrocytes Are Sensitive to Slightly Increased Concentrations of Heavy Metals.

Thyroid cancer incidence is markedly increased in volcanic areas where residents are biocontaminated by chronic lifelong exposure to slightly increased metals in the environment. Metals can influence the biology of living cells by a variety of mechanisms, depending not only on the dose and length of exposure but also on the type and stage of differentiation of target cells. We explored the effect of five heavy metals (Cu, Hg, Pd, W and Zn) at nanomolar concentrations (the biocontamination level in residents of the volcanic area in Sicily where thyroid cancer is increased) on stimulating the proliferation of undifferentiated (thyrospheres) and differentiated human thyroid cells. Thyrosphere proliferation was significantly increased after exposure to each individual metal and a greater stimulating effect was observed when a mixture of the examined metals was used. No effect was seen in differentiated thyrocytes. For all metals, the dose-response curve followed a biphasic pattern that is typical of hormesis. Thyrosphere growth concerned the size rather than number, except with the metal mixture. An altered morphology was also observed in metal-treated thyrospheres. Metal-induced proliferation was due to activation of the ERK1/2 pathway, as confirmed by growth inhibition when ERK1/2 signaling was blocked. These studies show that stem/precursor thyroid cells are sensitive to small increases in environmental metal concentrations that are harmless for differentiated thyrocytes.

Palladium-Induced Temporal Internalization of MHC Class I Contributes to T Cell-Mediated Antigenicity.

Palladium (Pd) is a widely used metal and extremely important biomaterial for the reconstruction of occlusions during dental restorations. However, metallic biomaterials can cause serious allergic reactions, such as Pd-related oral mucositis seen in dentistry. Metal allergy is categorized as a type IV allergy and we demonstrated that CD8 T cells play an important role in Pd allergy previously. As TCR of CD8 T cells recognizes MHC class I/peptide complex, the antigen specificity to this complex seems to be generated during Pd allergy. However, it remains unknown if Pd affects the MHC class I/peptide complex. In this study, we investigated the behavior of the MHC class I/peptide complex in response to Pd treatment. We found that PdCl2 treatment altered peptide presentation on MHC class I and that co-culture with Pd-treated DC2.4 cells induced activation of Pd-responsive TCR-expressing T cell line. Furthermore, PdCl2 treatment induced temporal MHC class I internalization and inhibition of membrane movement suppressed Pd-induced T cell-mediated antigenicity. These data suggest that Pd-induced MHC class I internalization is critical for generation of antigenicity through a mechanism including differential peptide loading on MHC class I, which results in Pd allergy.

Cross-Reactivity of Palladium in a Murine Model of Metal-Induced Allergic Contact Dermatitis.

Metal allergy is usually diagnosed by patch testing, however, the results do not necessarily reflect the clinical symptoms because of cross-reactivity between different metals. In this study, we established the novel mouse model of cross-reactive metal allergy, and aimed to elucidate the immune response in terms of T-cell receptor repertoire. This model was classified into two groups: the sensitization to nickel and challenge with palladium group, and the sensitization to chromium and challenge with palladium group. This model developed spongiotic edema with intra- and peri-epithelial infiltration of CD4+ T cells in the inflamed skin that resembles human contact dermatitis. Using T cell receptor analysis, we detected a high proportion of T cells bearing Trav8d-1-Traj49 and Trav5-1-Traj37 in the Ni- and Cr-sensitized Pd-challenged mice. Furthermore, mucosal-associated invariant T cells and invariant natural killer T cells were also detected. Our results indicated that T cells bearing Trav8d-1-Traj49 and Trav5-1-Traj37 induced the development of palladium-cross reactive allergy, and that mucosal-associated invariant T and invariant natural killer T cells were also involved in the cross-reactivity between different metals.

Patch Testing With an Extended Metal Allergen Series at the Massachusetts General Hospital (2006-2017).

BACKGROUND: Reports of patch test data with an extended metal series that includes rare metals are limited. OBJECTIVE: The aims of the study were to analyze and report patch testing results from an extended metal series, examine associations with sex and age, and highlight concomitant metal reactions. METHODS: This study is a retrospective review of 150 patients referred for suspected metal allergy from January 1, 2007, to December 31, 2016. RESULTS: The most common indications for evaluation referral were those having symptoms after implantation of a metal device (55.3%) and those with a history and concern of metal allergy before implantation of a metal device (22.0%). One or more positive patch test reactions were observed in 87 patients (58.0%). Metals with the highest frequencies were nickel sulfate 2.5% (26.2%), gold sodium thiosulfate 0.5% (23.0%), gold sodium thiosulfate 2.0% (20.7%), palladium chloride 2.0% (19.6%), cobalt chloride 1.0% (12.0%), and manganese chloride 2.0% (10.1%). Of the 45 metals tested, 15 caused no patch test reactions. Female patients were more likely to be sensitized to nickel, gold, and palladium (P < 0.05). Younger patients (≤40 years) had higher reaction rates to nickel, mercury, palladium, and cobalt. Concomitant reactions of the top metals (nickel, palladium, gold, and cobalt) were statistically associated bidirectionally (P < 0.05), except for cobalt and gold. CONCLUSIONS: Allergy to metals, including those not included in standard series, may be more prevalent than previously suspected. Results may help guide future testing for suspected metal allergy, although future studies are warranted.

New in vitro highly cytotoxic platinum and palladium cyanoximates with minimal side effects in vivo.

Several biologically active bivalent Pd and Pt complexes with two structurally similar cyanoxime ligands abbreviated as H(DECO): 2-oximino-2-cyano-N,N'-diethylacetamide, and H(PyrCO): 2-oximino-2-cyan-N-pyrrolidine acetamide were synthesized and characterized using spectroscopic methods, thermal analysis and X-ray crystallography. Structures revealed planar cis-geometry of studied complexes. Freshly obtained Pt(DECO)2, Pd(DECO)2, Pt(PyrCO)2 and Pd(PyrCO)2 complexes were used in for in vitro cytotoxicity assays using two different etiology human cancer cell lines HeLa and WiDr cells. Investigated compounds showed cytotoxicity levels at or above cisplatin. Pt(DECO)2 was also tested in vivo in healthy C57BL/6 mice. The complex was administered at three different dosage (0, 7.5, 15 mg/kg, i.p. once/week), over a total period of 8 weeks. No changes were observed in the animal weight in the treated mice compared to the control dextrose-treated group. The levels of erythrocytes, leukocytes, and hemoglobin were within the normal level suggesting low myelotoxicity. Negligible cardiotoxicity was observed from the histological evaluation of the hearts from the treated animals. Results from the tail nerve conduction velocity (NCV) and nerve histomorphometry suggested no impact of Pt(DECO)2 on peripheral nerves. The complex, however, induced certain hepatotoxicity and lead to the elevation of IL-6, a pro-inflammatory cytokine. Overall, Pt(DECO)2 showed minimal in vivo toxicity, thus presenting a promising candidate for future testing in animal models of cancer.

Higher Prevalence of Nickel and Palladium Hypersensitivity in Patients with Ulcerative Colitis.

BACKGROUND: The etiology of ulcerative colitis (UC) remains elusive even though many genetic and environmental pathogenic factors have been reported. Aberrant inflammatory responses mediated by specific subsets of T cells have been observed in ulcerative lesions of UC patients. OBJECTIVES: To elucidate the involvement of a delayed-type hypersensitivity reaction in UC, we focused on dental metal hypersensitivity, a T cell-mediated, delayed-type allergic reaction that causes oral contact mucositis and systemic cutaneous inflammation. METHOD: We recruited 65 Japanese UC patients and 22 healthy controls (HC) and used the in vitro lymphocyte stimulation test to quantify their sensitivity to zinc, gold, nickel, and palladium - the metals that have been widely used in dentistry. All subjects were users of metallic dental implants and/or prostheses containing zinc, gold, nickel, and/or palladium as major constituents. RESULTS: Sixty percent of the UC patients were hypersensitive to at least one metal species, whereas 32% of the HC were hypersensitive to only a single metal species. The overall incidence of metal hypersensitivity was significantly higher for UC patients than for HC. Furthermore, a significantly greater proportion of UC patients were hypersensitive to nickel or palladium. The severity of the sensitivity to nickel and palladium was also significantly greater for UC patients than for HC. CONCLUSIONS: This pilot study demonstrates that UC patients have a significantly higher incidence of hypersensitivity to nickel and palladium, suggesting the possible involvement of dental metal hypersensitivity in UC pathogenesis.

Palladium causes bizarre skin hyperpigmentation in long-term dihydrocodeinone 'Braun' abusers.

BACKGROUND: 'Braun' is an illegal injectable dihydrocodeinone-enriched drug mixture of semi-synthetic opioids. It is prepared by palladium-catalysed hydrogenation from codeine-containing tablets. OBJECTIVE: We aimed to characterize the dermatologic consequences of long-term abuse of 'Braun'. METHODS: Skin biopsies of two long-term 'Braun' abusers were evaluated histopathologically, immunohistochemically and ultrastructurally. Palladium skin content was assessed by X-ray fluorescence (XRF) spectrometry. RESULTS: Both patients showed generalized diffuse dark blue-grey hyperpigmentation of the skin. In both, an abnormal population of cells containing intracytoplasmic brownish granular material was identified in the papillary dermis by light microscopy. Electron microscopy revealed a dense and minimally structured material that predominantly accumulated in macrophages, fibroblasts and vascular endothelial cells. XRF analysis confirmed elevated levels of palladium in the patient's skin in comparison to healthy controls. CONCLUSION: Long-term abuse of palladium-contaminated dihydrocodeinone ('Braun') results in excessive accumulation of granular material in various dermal cell types and causes generalized diffuse skin hyperpigmentation.

Analysis of Spatial Dose-Volume Relationships and Decline in Sexual Function Following Permanent Brachytherapy for Prostate Cancer.

OBJECTIVE: To explore relationships between dose to periprostatic anatomic structures and erectile dysfunction (ED) outcomes in an institutional cohort treated with prostate brachytherapy. METHODS: The Sexual Health Inventory for Men (SHIM) instrument was administered for stage cT1-T2 prostate cancer patients treated with Pd-103 brachytherapy over a 10-year interval. Dose volume histograms for regional organs at risk and periprostatic regions were calculated with and without expansions to account for contouring uncertainty. Regression tree analysis clustered patients into ED risk groups. RESULTS: We identified 115 men treated with definitive prostate brachytherapy who had 2 years of complete follow-up. On univariate analysis, the subapical region (SAR) caudal to prostate was the only defined region with dose volume histograms parameters significant for potency outcomes. Regression tree analysis separated patients into low ED risk (mean 2-year SHIM 20.03), medium ED risk (15.02), and high ED risk (5.54) groups. Among patients with good baseline function (SHIM ≥ 17), a dose ≥72.75 Gy to 20% of the SAR with 1 cm expansion was most predictive for 2-year potency outcome. On multivariate analysis, regression tree risk group remained significant for predicting potency outcomes even after adjustment for baseline SHIM and age. CONCLUSION: Dose to the SAR immediately caudal to prostate was predictive for potency outcomes in patients with good baseline function. Minimization of dose to this region may improve potency outcomes following prostate brachytherapy.

Prevalence of contact allergy to metals: nickel, palladium, and cobalt in Southern Sweden from 1995-2016.

BACKGROUND: In 2001, the EU nickel directive was introduced to prevent contact allergy to nickel. Contact allergy to palladium and/or cobalt is often seen together with contact allergy to nickel. OBJECTIVES: To compare the contact allergy prevalence of nickel, palladium, and cobalt allergy before and after the introduction of the EU nickel directive in consecutive patients with dermatitis. METHODS: A retrospective analysis of patch test results from 1995-2016 was performed (n = 18 264). Chi-square tests were used to examine trends for nickel, palladium, and cobalt across test years. Logistic regression was used for associations. RESULTS: The prevalence of nickel allergy decreased significantly in the youngest age group (6-30 years) for both female and male patients from 1995-1999 to 2012-2016: females: 33.4% to 19.1% (P < .001); males: 5.9% to 2.1% (P < .05). The concomitant reactions between nickel and palladium and nickel and cobalt among young females, respectively, also decreased significantly. Isolated palladium and cobalt allergy remained stable (1.4% and 2.3%, respectively) during the same time period for both men and women. CONCLUSIONS: The prevalence of nickel has decreased among young females and males suspected of contact allergy in Southern Sweden after the introduction of the EU nickel directive. There has been no change in isolated palladium or cobalt allergy.

Delayed hypersensitivity to palladium dichloride: 15-year retrospective study in a skin allergy unit.

BACKGROUND: Metal allergies are the most frequent causes of allergic contact dermatitis. Although the use of palladium is increasing, it is not included in any baseline series. OBJECTIVE: To assess the prevalence of hypersensitivity to palladium and to describe the clinical and demographic characteristics of patients who are sensitized to palladium dichloride (PdCl2 ). METHODS: A single-centre, retrospective study of 15 years of patch testing with the Spanish baseline series supplemented with PdCl2 2% pet. was performed. We collected clinical and demographic data and data on co-sensitization among the metals studied, and we compared patients who were sensitized to palladium, with or without co-sensitization to nickel, with the rest of the study population. RESULTS: Among the 3678 included patients, 730 (19.9%) were sensitized to nickel sulfate. The prevalence of sensitization to PdCl2 (n = 316, 8.6%) was higher than the prevalence of sensitization to potassium dichromate (n = 240, 6.5%) and similar to the prevalence of sensitization to cobalt chloride (n = 353, 9.6%). Only 26 (8.2%) of the patients sensitized to palladium were not co-sensitized to nickel. The percentage of men and patients aged ≥40 years was higher in this subgroup than in the patients with nickel co-sensitization. CONCLUSIONS: Given the high prevalence of hypersensitivity to PdCl2 , this metal salt should be included in the Spanish baseline series, notwithstanding the frequency of co-sensitization to nickel.

A new cationic palladium(II) dithiocarbamate exhibits anti-inflammatory, analgesic, and antipyretic activities through inhibition of inflammatory mediators in in vivo models.

Inflammation is being a protective mechanism of the body towards the injury. However, chronic and progressive inflammation may lead to some chronic diseases. Due to the serious unwanted effects associated with available drugs, new and safe anti-inflammatory agents are still required. Therefore, the present study was designed to investigate the anti-inflammatory, analgesics, and antipyretic properties of a new compound (4-benzylpiperidine-1-carbodithioato-κ2S,S')(1,4-bis-(diphenylphosphino)butane)palladium(II)chloride monohydrate (compound-1) in albino mice models. Compound-1 was characterized by elemental analysis, FT-IR, and multinuclear NMR spectroscopy. Initially, compound-1 was evaluated for cytotoxicity, anti-inflammatory, and analgesic activities by performing MTT assay, carrageenan-, histamine-, serotonin-, and CFA-induced paw edema, mechanical hyperalgesia, thermal hyperalgesia, and mechanical allodynia (0.1, 1, and 10 mg/kg, b.w). Antipyretic activity was evaluated in brewer's yeast-induced model. The pro-inflammatory cytokines were measured by using commercially available ELISA kits. Additionally, nitrite production, antioxidant enzymes, H&E staining, muscle activity and motor coordination, and kidney and liver function tests were also determined. The results demonstrated that compound-1 significantly inhibited inflammation, pain, and febrile responses in all models at a dose of 10 mg/kg without effecting viability of cells in vitro at concentrations up to 100 µM. Similarly, the data clearly demonstrated significant reduction in the pro-inflammatory cytokines and nitrite production while enhancing antioxidant enzymes. Furthermore, pretreatment with compound-1 did not produce any prominent side effect on kidney, liver, stomach, and muscles. These findings suggest that compound-1 has potent anti-inflammatory-, pain-, and pyrexia-relieving properties. Hence, compound-1 might be a potential candidate for the therapeutic management of chronic inflammation and pain.

Associations of Nickel Co-Reactions and Metal Polysensitization in Adults.

BACKGROUND: Allergic contact dermatitis to metals is a significant clinical and public health problem. Little is known about the determinants of polysensitization to metals. OBJECTIVE: The aim of the study was to determine the frequency and predictors of nickel co-reactions and metal polysensitization. METHODS: This is a retrospective chart review of 686 adults (age ≥ 18 years) who were patch tested from 2014 to 2017. RESULTS: Overall, 267 patients (38.9%) had 1 or more positive patch-test reactions to a metal allergen, most commonly nickel (17.4%), mercury (12.3%), and palladium (9.2%). Nickel reactions were inversely associated with age (logistic regression; adjusted odds ratio [95% confidence interval], 0.39 [0.29-0.78]). Among patients with positive reactions to nickel, 34.5%, 15.1%, and 5.0% had positive reactions to 1, 2, or 3 additional metals, respectively. The most common nickel co-reactors were palladium, mercury, and gold. Polysensitization to metals occurred in 11.8% of patients. Polysensitization to metal allergens was associated with female sex (6.67 [1.01-44.21]) and inversely associated with age (0.40 [0.18-0.88]). CONCLUSIONS: Nickel-sensitized patients have high rates of metal co-reactions. Polysensitization to metals is common in adults. These results may help guide future strategies for allergen avoidance.

Comparative outcomes and toxicities for ruthenium-106 versus palladium-103 in the treatment of choroidal melanoma.

For the treatment of choroidal melanoma, palladium-103 (Pd) and ruthenium-106 (Ru) plaque brachytherapy shows reduced toxicity compared with the historical standard iodine-125. No report has directly compared the clinical outcomes between Pd and Ru, and the reasons for the selection of one over the other remain purely theoretical. Patients with choroidal melanoma with apical tumor height up to 5 mm were included. Patients from Emory University were treated with Pd between 1993 and 2012. Patients from Cleveland Clinic were treated with Ru between 2005 and 2010. Medical records were retrospectively reviewed. We compared post-treatment visual acuity (VA), toxicity, and oncologic outcomes. Pd patients (n=124) and Ru patients (n=42) had a median follow-up of 4.2 and 5.0 years, respectively. Radiation retinopathy-free survival was similar for both radioisotopes, but Ru had lower grades of retinopathy (P=0.006). Pd was associated with worse VA preservation (≥20/40) by year 3 (odds ratio: 3.8; 95% confidence interval: 1.01-14.31, P=0.048). Pd was associated with higher distant metastases-free survival (DMFS) in multivariate analysis (hazard ratio: 0.10; 95% confidence interval: 0.02-0.38; P<0.001). Ru had lower grades of radiation retinopathy and improved long-term VA preservation, but also inferior DMFS, compared with Pd. Because of the inherent limitations of a retrospective analysis, the significance of the inferior DMFS for Ru remains unclear, although the suggestion of a slight inferiority in terms of DMFS for Ru is consistent with the other limited literature. On the basis of this study, we believe that both radioisotopes remain appropriate for the treatment of small choroidal melanomas up to 5 mm in apical height.

Placement of an absorbable rectal hydrogel spacer in patients undergoing low-dose-rate brachytherapy with palladium-103.

PURPOSE: Rates of rectal toxicity after low-dose-rate (LDR) brachytherapy for prostate cancer are dependent on rectal dose, which is associated with rectal distance from prostate and implanted seeds. Placement of a hydrogel spacer between the prostate and rectum has proven to reduce the volume of the rectum exposed to higher radiation dose levels in the setting of external beam radiotherapy. We present our findings with placing a rectal hydrogel spacer in patients following LDR brachytherapy, and we further assess the impact of this placement on dosimetry and acute rectal toxicity. METHODS AND MATERIALS: Between January 2016 and April 2017, 74 patients had placement of a hydrogel spacer, immediately following a Pd-103 seed-implant procedure. Brachytherapy was delivered as follows: as a monotherapy to 26 (35%) patients; as part of planned combination therapy with external beam radiotherapy to 40 (54%) patients; or as a salvage monotherapy to eight (11%) patients. Postoperative MRI was used to assess separation achieved with rectal spacer. Acute toxicity was assessed retrospectively using Radiation Oncology Therapy Group radiation toxicity grading system. Rectal dosimetry was compared with a consecutive cohort of 136 patients treated with seed implantation at our institution without a spacer, using a 2-tailed paired Student's t test (p < 0.05 for statistical significance). RESULTS: On average, 11.2-mm (SD 3.3) separation was achieved between the prostate and the rectum. The resultant mean rectal volume receiving 100% of prescribed dose (V100%), dose to 1 cc of rectum (D1cc), and dose to 2 cc of rectum (D2cc) were 0 (SD 0.05 cc), 25.3% (SD 12.7), and 20.5% (SD 9.9), respectively. All rectal dosimetric parameters improved significantly for the cohort with spacer placement as compared with the nonspacer cohort. Mean prostate volume, prostate V100 and dose to 90% of gland (D90) were 29.3 cc (SD 12.4), 94.0% (SD 3.81), and 112.4% (SD 12.0), respectively. Urethral D20, D5cc, and D1cc were 122.0% (SD 17.27), 133.8% (SD 22.8), and 144.0% (SD 25.4), respectively. After completing all treatments, at the time of first the followup, 7 patients reported acute rectal toxicity-6 experiencing Grade 1 rectal discomfort and 1 (with preexisting hemorrhoids) experiencing Grade 1 bleeding. CONCLUSIONS: Injection of rectal spacer is feasible in the post-LDR brachytherapy setting and reduces dose to the rectum with minimal toxicity. Prostate and urethral dosimetries do not appear to be affected by the placement of a spacer. Further studies with long-term followup are warranted to assess the impact on reduction of late rectal toxicity.

The biodistribution, excretion and potential toxicity of different-sized Pd nanosheets in mice following oral and intraperitoneal administration.

Two-dimensional (2D) Pd-based nanomaterials with strong near-infrared absorption have recently shown great application prospects in cancer diagnosis and therapy. Most previous studies mainly focused on understanding the in vivo behaviors and treatment effects of these Pd-based nanomaterials after intravenous injection into mice. However, it remains unclear whether other administration routes will affect the in vivo biodistribution, excretion and potential toxicity of Pd-based nanomaterials. In this study, for the first time we systematically explored the in vivo behaviors of different-sized Pd nanosheets (NSs) (approximately 5 nm, 30 nm and 80 nm) following oral feeding and intraperitoneal injection. It was found that Pd NSs with oral administration had a rather low accumulation that decreased with time in all examined organs, and became almost undetectable in these organs at 24 h post-injection. In comparison, the intraperitoneally injected Pd NSs exhibited obvious time-dependent and size-dependent accumulations in the reticuloendothelial (RES) system including the liver and spleen within 24 h post-injection, and then the accumulation amounts decreased with the lapse of time. Moreover in tumor tissue, smaller-sized Pd NSs (5 nm) had a higher uptake than larger-sized Pd NSs (30 nm and 80 nm). Excretion studies uncovered that more than 70% ID of Pd NSs could be rapidly excreted from the body through urine and feces within two days after oral administration, whereas Pd NSs with intraperitoneal injection could be gradually cleared, mainly via urine within 8 days. Further histological examination of organ sections and blood biochemical analysis evidenced that these different-sized Pd NSs do not cause obvious toxicity in the treated mice at the tested period with the given dose. These results not only indicate that the biodistribution and excretion capabilities of Pd NSs are closely related to their administration routes, but also imply that the intraperitoneally injected Pd NSs have greater potential for in vivo biomedical studies compared to oral feeding, because of their relatively higher tissue absorption and gradual excretion from the body. This study will provide valuable information for the clinical translation of 2D Pd-based nanomaterials.