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Elevated Blood Cadmium and Lead Levels in Chronic Pruritic Dermatoses

Open ArchivePublished:June 26, 2019DOI:https://doi.org/10.1016/j.jid.2019.06.130
      To the Editor
      Increased energy consumption and rapid urbanization have exposed human skin to unprecedented levels of air, soil, and water pollution (
      • Puri P.
      • Nandar S.K.
      • Kathuria S.
      • Ramesh V.
      Effects of air pollution on the skin: a review.
      ). Skin is exposed to pollutants through both direct exposure and systemic distribution after inhalation or ingestion (
      • Araviiskaia E.
      • Berardesca E.
      • Bieber T.
      • Gontijo G.
      • Sanchez Viera M.
      • Marrot L.
      • et al.
      The impact of airborne pollution on skin.
      ). These pollutants can impair cutaneous barrier function, activate inflammatory pathways, induce oxidative stress, and influence the immune response (
      • Puri P.
      • Nandar S.K.
      • Kathuria S.
      • Ramesh V.
      Effects of air pollution on the skin: a review.
      ). Studies have shown that exposure to pollutants can lead to the development and worsening of dermatologic conditions, including acne and skin cancer (
      • Kim K.E.
      • Cho D.
      • Park H.J.
      Air pollution and skin diseases: adverse effects of airborne particulate matter on various skin diseases.
      ). However, few large-scale epidemiological studies have assessed the association between blood heavy metal levels and chronic pruritic dermatoses. Given that cutaneous nerve fibers traverse close to the external skin barrier, we hypothesized that pruritic dermatoses would be more frequent in patients exposed to specific pollutants. Herein, we investigate the association between chronic pruritic skin eruptions and blood levels of cadmium, lead, and mercury, which are common toxins associated with occupational exposure and industrial waste.
      We first conducted a literature review using EMBASE, PubMed, and MEDLINE, with the following keywords: heavy metals, cadmium, lead, skin, rash, pruritus, and itch. We also conducted a cross-sectional analysis of the data from the National Health and Nutrition Examination Survey study, which was collected by the National Center for Health Statistics from 2005 to 2006 (

      CDC. National health and nutrition examination survey data. Hyattsville, MD; 2006.

      ) and approved by its institutional review board. Presence of chronic pruritic dermatoses was assessed by participants answering affirmatively to having “an itchy rash which was coming and going for at least 6 months” at some point within the year prior. This cohort was compared both to participants reporting asthma, given the detrimental effect of pollution on asthma, and a healthy control group without asthma or pruritic dermatoses (
      • Jiang X.Q.
      • Mei X.D.
      • Feng D.
      Air pollution and chronic airway diseases: what should people know and do?.
      ).
      Whole blood samples were collected by certified phlebotomists trained in standardized laboratory procedures. Prescreened polyethylene vials and vacutainers stored at –20 °C were required for the specimen. All samples underwent extensive quality control procedures ensuring no background contamination. Any variation in procedure, equipment, storage, or transport resulted in specimen rejection by the lab. Unscheduled quality assurance site visits confirmed that all protocols met the 1988 Clinical Laboratory Improvement Act requirements. Heavy metal measurements were made with a PerkinElmer (model SIMAA 6000) simultaneous multielement atomic absorption spectrometer and inductively coupled plasma-mass spectrometer. Continuous data and categorical data were analyzed with Student t test and χ2 test, respectively. Associations were determined with multiple logistic regression reporting odds ratios weighted to the US Census. Two-sided P-values <0.05 indicate statistical significance.
      Our literature review yielded 1,221 articles after removing duplicates. Unrelated pollutants, non-skin diseases, and nonhuman research were excluded; seven studies were included in our review. Although increased blood heavy metal levels were not found to be associated with eczema, increased exposure to lead (P = 0.008), copper (P = 0.04), and zinc (P = 0.01) was associated with more severe eczema (
      • Kathuria P.
      • Silverberg J.I.
      Association of pollution and climate with atopic eczema in US children.
      ;
      • Wei J.
      • Zhang J.J.
      • Ji J.S.
      Association of environmental exposure to heavy metals and eczema in US population: Analysis of blood cadmium, lead, and mercury.
      ). A study investigating arsenic found that increased exposure was associated with more severe hyperkeratotic skin lesions and pruritus (P < 0.05) (
      • Mitra A.K.
      • Bose B.K.
      • Kabir H.
      • Das B.K.
      • Hussain M.
      Arsenic-related health problems among hospital patients in southern Bangladesh.
      ). An observational study of nickel-cadmium battery workers reported pruritus and skin eruptions in 97.4% of subjects (
      • Bar-Sela S.
      • Levy M.
      • Westin J.B.
      • Laster R.
      • Richter E.D.
      Medical findings in nickel-cadmium battery workers.
      ). Tannery workers with increased serum chromium (P < 0.05) were found to have increased cutaneous complaints of rough skin, itch, and rash (P < 0.001;
      • Islam L.N.
      • Rahman F.
      • Hossain A.
      Serum immunoglobulin levels and complement function of tannery workers in Bangladesh.
      ). Ocular pruritus was also found to be associated with aerial heavy metal exposure (
      • Nguyen T.T.T.
      • Higashi T.
      • Kambayashi Y.
      • Anyenda E.O.
      • Michigami Y.
      • Hara J.
      • et al.
      A longitudinal study of association between heavy metals and itchy eyes, coughing in chronic cough patients: related with non-immunoglobulin E mediated mechanism.
      ). Finally, blood lead levels have been found to be a positive predictor of uremic pruritus in patients undergoing hemodialysis (
      • Weng C.H.
      • Hsu C.W.
      • Hu C.C.
      • Yen T.H.
      • Chan M.J.
      • Huang W.H.
      Blood lead level is a positive predictor of uremic pruritus in patients undergoing hemodialysis.
      ).
      In our National Health and Nutrition Examination Survey analysis, there were 10,348 survey respondents. We excluded 1,941 participants lacking laboratory data and 260 participants with incomplete questionnaires. Of the 8,147 eligible subjects with complete data, 473 (5.8%) reported chronic pruritic dermatoses. Demographic characteristics (Table 1) showed higher mean age with pruritic dermatoses but no significant difference in the sex, race, smoking status, heart disease history, or cancer history. Mean blood cadmium levels were 18.4% (P = 0.0039) higher in pruritic dermatoses compared with healthy controls, and 8.3% (P = 0.26) higher than asthma patients. Mean blood lead levels in pruritic dermatoses were 9.9% (P = 0.0366) higher than healthy controls, and 28.2% (P < 0.0001) higher than asthma patients. Mean blood mercury levels in pruritic dermatoses were 11.2% (P = 0.1023) and 20.5% (P = 0.0270) higher than healthy controls and asthma patients, respectively (Table 1). Multiple logistic regression, adjusted for age, sex, race, education, asthma, and smoking status, showed an association between pruritic dermatoses and increased blood cadmium levels (odds ratio = 1.23; 95% confidence interval = 1.02–1.48). A separate multiple logistic regression using the same variables also identified an association with increased blood lead levels (odds ratio = 1.07; 95% confidence interval = 1.01–1.13). An association with mercury levels was not observed (odds ratio = 1.03; 95% confidence interval = 0.97–1.09; Figure 1).
      Table 1Demographics and Blood Toxin Levels
      CharacteristicsHealthy (n = 6,631)Pruritic Dermatoses (n = 473)Asthma (n = 1,043)
      P-value Compared with Healthy ControlsP-value Compared with Pruritic DermatosesP-value Compared with Healthy Controls
      Age, years30.1033.130.00626.850.00010.001
      Gender, n (%)0.8320.7380.433
       Men3,219 (48.54)232 (49.05)597 (49.96)
       Women3,412 (51.46)241 (50.95)498 (50.04)
      Race, n (%)0.0510.214<0.0001
       Non-Hispanic white2,562 (38.64)201 (42.49)487 (40.75)
       Non-Hispanic black1,675 (25.26)128 (27.06)384 (32.13)
       Hispanic2,090 (31.52)119 (25.16)263 (22.01)
       Other304 (4.58)25 (5.29)61 (5.10)
      Married, n (%)2,027 (30.47)146 (30.87)0.892263 (22.01)<0.0001<0.0001
      Heart disease, n (%)129 (3.61)15 (5.49)0.11529 (5.15)0.8350.006
      Cancer, n (%)282 (7.88)24 (8.70)0.62854 (9.52)0.6970.038
      Smoker, n (%)760 (11.46)67 (14.16)0.077144 (12.05)0.2420.243
      Mean blood levels
       Cadmium (μg/l)0.3760.4450.0040.4110.2600.049
       Lead (μg/l)1.7041.8720.0371.460<0.0001<0.0001
       Mercury (μg/l)1.1211.2460.1021.0340.0270.072
      P-values reflect Pearson chi-squared test for categorical variables and Student t test for continuous variables. Boldface indicates statistical significance defined as P < 0.05.
      Figure thumbnail gr1
      Figure 1Mean blood toxin levels with OR of pruritic dermatoses. Mean comparison of blood toxin levels was conducted with Student t tests. OR reflect multiple logistic regression weighted to reflect the US Census. Adjustments were made for age, sex, race, education, asthma, and smoking status. *P < 0.05, ***P < 0.001. OR, odds ratio.
      Although multiple studies have reported associations between pollutants and cutaneous disease, the underlying mechanism remains unclear (
      • Araviiskaia E.
      • Berardesca E.
      • Bieber T.
      • Gontijo G.
      • Sanchez Viera M.
      • Marrot L.
      • et al.
      The impact of airborne pollution on skin.
      ;
      • Kim K.E.
      • Cho D.
      • Park H.J.
      Air pollution and skin diseases: adverse effects of airborne particulate matter on various skin diseases.
      ,
      • Weng C.H.
      • Hsu C.W.
      • Hu C.C.
      • Yen T.H.
      • Chan M.J.
      • Huang W.H.
      Blood lead level is a positive predictor of uremic pruritus in patients undergoing hemodialysis.
      ). Previous studies have described non-IgE–mediated mechanisms of pruritus with heavy metal exposure, suggesting that heavy metals may have a direct role that needs to be elucidated in further studies (
      • Nguyen T.T.T.
      • Higashi T.
      • Kambayashi Y.
      • Anyenda E.O.
      • Michigami Y.
      • Hara J.
      • et al.
      A longitudinal study of association between heavy metals and itchy eyes, coughing in chronic cough patients: related with non-immunoglobulin E mediated mechanism.
      ,
      • Weng C.H.
      • Hsu C.W.
      • Hu C.C.
      • Yen T.H.
      • Chan M.J.
      • Huang W.H.
      Blood lead level is a positive predictor of uremic pruritus in patients undergoing hemodialysis.
      ). Whereas our results reveal an age differential between our cohorts, previous literature reveals no association between age and blood heavy metal levels (
      • Chang L.
      • Shen S.
      • Zhang Z.
      • Song X.
      • Jiang Q.
      Study on the relationship between age and the concentrations of heavy metal elements in human bone.
      ). However, chronic exposure may be related to age of participants and could be further studied by investigating bone heavy metal concentrations (
      • Chang L.
      • Shen S.
      • Zhang Z.
      • Song X.
      • Jiang Q.
      Study on the relationship between age and the concentrations of heavy metal elements in human bone.
      ).
      Lead inhalation and ingestion is attributed to tobacco, construction, hazardous waste, and industrial sites making batteries, ammunition, and roofing materials, whereas cadmium may be ingested from vegetables contaminated with fertilizer (
      • Krueger W.S.
      • Wade T.J.
      Elevated blood lead and cadmium levels associated with chronic infections among non-smokers in a cross-sectional analysis of NHANES data.
      ). Even chronic, low dose heavy metal exposure poses a substantial public health concern because chronic inflammatory skin diseases are exacerbated with pollution exposure (
      • Araviiskaia E.
      • Berardesca E.
      • Bieber T.
      • Gontijo G.
      • Sanchez Viera M.
      • Marrot L.
      • et al.
      The impact of airborne pollution on skin.
      ;
      • Wang G.
      • Fowler B.A.
      Roles of biomarkers in evaluating interactions among mixtures of lead, cadmium and arsenic.
      ). As such, physicians should consider screening patients presenting with chronic pruritic dermatoses of uncertain etiology for pollution exposure given the association of elevated lead and cadmium levels in these patients.

      Data availability statement

      Datasets related to this article can be found at https://wwwn.cdc.gov/nchs/nhanes/continuousnhanes/ hosted by the National Center for Health Statistics (

      CDC. National health and nutrition examination survey data. Hyattsville, MD; 2006.

      ).

      Conflict of Interest

      SGK is on the advisory board for Menlo and Trevi Therapeutics and has received grant funding from Kiniksa Pharmaceuticals. He is also the recipient of a Dermatology Foundation Medical Dermatology Career Development Award. SK is an advisory board member of Almirall, Menlo, Sun Pharma, and Unilever. The other authors have no conflict of interest to declare.

      Acknowledgments

      The content in this manuscript has not been published or submitted for publication elsewhere. All authors have contributed significantly and are in agreement with the content of the manuscript.

      Author Contributions

      Conceptualization: SGK, SPP; Data Curation: SPP; Formal Analysis: SPP; Methodology: SGK, SK, SPP; Supervision: SGK, SK; Visualization: SPP, RK, MB; Writing - Original Draft Preparation: SPP, RK, MB; Writing - Review and Editing: SPP, RK, MB, SK, SGK.

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