DOI: 10.5061/dryad.tht76hdz4
title: The relationship between heavy metal exposure and type 2 diabetes: a large-scale retrospective cohort study using occupational health examinations

description: Objectives: To investigate the associations between heavy metal exposure
 and serum ferritin levels, physical measurements, and type 2 diabetes
 mellitus (DM). Design: A retrospective cohort study. Setting: Changwon,
 the location of this study, is a Korean representative industrial city.
 Data were obtained from medical check-ups between 2002 and 2018.
 Participants: A total of 34,814 male subjects were included. Of them,
 1,035 subjects with lead exposure, 200 subjects with cadmium exposure, and
 the 33,579 remaining were assigned to cohort A, cohort B, and the control
 cohort, respectively. Data including personal history of alcohol and
 smoking, age, height, weight, the follow-up duration, HbA1c, fasting blood
 sugar (FBS), ferritin levels, and lead and cadmium levels within one year
 after exposure were collected.  Primary Outcome Measure: In
 subjects without diabetes, changes in FBS and HbA1c were analyzed through
 repeated tests at intervals of one year or longer after the occupational
 exposure to heavy metals. Results: In cohort A, DM was diagnosed in 33
 subjects. There was a significant difference in lead concentrations
 between the subjects diagnosed with DM and those without DM during the
 follow-up period (3.94 ± 2.92 mg/dL versus 2.81 ± 2.03 mg/dL, p = 0.002).
 Simple exposure to heavy metals (lead and cadmium) was not associated with
 DM in Cox regression models (lead exposure hazard ratio [HR] 1.01, 95% CI
 0.58 – 1.77, p 0.971; cadmium exposure HR 1.48, 95% CI: 0.61 – 3.55, p =
 0.385). Annual changes in FBS according to lead concentration at the
 beginning of exposure showed a positive correlation (r = 0.072, p =
 0.032). Conclusion: Our findings demonstrated that simple occupational
 exposure to heavy metals lead and cadmium was not associated with the
 incidence of DM. However, lead concentrations at the beginning of the
 exposure might be an indicator of DM and glucose elevations.
description: <strong>Study population</strong> Changwon,
 the location of this study, is a representative industrial city in Korea.
 Many occupations involve heavy metal exposure, including employees of
 battery-manufacturing plants. This cohort study was based on the data from
 occupational health examinations (n = 403,253) conducted from 2002 to 2018
 in subjects with jobs related to heavy metals. A schematic flow chart for
 the selection of subjects is shown in Figure 1. All participants underwent
 a physical examination with a blood sample taken in the morning following
 an overnight fast. They also filled out a questionnaire. Among these
 403,253 subjects, 89,826 who had ferritin blood levels measured were
 included and 38,039 women were excluded. In occupational screening, most
 women were fertile. The ferritin results might be low because of
 menstruation. A total of 269 subjects were excluded because of the
 unavailability of HbA1c or FBS data. Furthermore, 2709 subjects who were
 already diagnosed with DM were excluded (DM was defined as FBS ≥ 126
 mg/dl, HbA1c ≥ 6.5%, or a history of DM reported in the questionnaire).
 Additionally, 28,151 subjects were excluded because they only had one
 screening result without follow-up data. Finally, 34,814 subjects were
 included in the analysis. Of these, 1,035 subjects with lead exposure, 200
 subjects with cadmium exposure, and the 33,579 remaining subjects were
 assigned to cohort A, cohort B, and the control cohort, respectively. This
 study collected subject data including age, HbA1c, FBS, ferritin levels,
 height, body weight, the follow-up duration, and the concentrations of
 heavy metals (lead and cadmium). The study protocol was approved by the
 Institutional Review Board (IRB) of Samsung Changwon Medical Center
 (SCMC-2019-04-014). All participants provided written informed consent for
 the use of their data.    
 <strong>Data collection</strong> This
 study was based on data from occupational health examinations already
 conducted. The health check-up data included objective numerical data such
 as blood tests, imaging tests, and physical examinations, as well as the
 questionnaire responses of the subjects. The questionnaire included items
 on personal history, physical activity, systemic symptoms, sleep patterns,
 stress, anxiety, depression, gambling, and job stress. All data were
 computerized. The authors analysed the demographic information, physical
 examination results, past history, and laboratory results (HbA1c, blood
 glucose, ferritin, lead, and cadmium levels). After obtaining IRB
 approval, two authors (JHJ and MHJ) independently analysed the data.
 <strong>Measuring
 blood levels of lead and cadmium</strong> To
 measure the blood levels of lead and cadmium, 3 ml of blood was collected
 from each subject into vacuum bottles using heparin as an anticoagulant in
 the morning following an overnight fast. Blood samples were diluted 1:15
 and 1:10 to measure the lead and cadmium concentrations, respectively,
 with 2.5 ml of 10% Triton X-100, 0.1 ml of concentrated nitric acid, and 1
 ml of 10% ammonium di-hydrogen phosphate as a modifier. Graphite-furnace
 atomic absorption spectrometry with Zeeman background correction (PinAAcle
 9i00z Atomic absorption spectrometer, PerkinElmer, Norwalk, Connecticut,
 USA) was used to measure the lead and cadmium levels in all subjects
 within the first year of heavy metal exposure. The minimum detectable
 limits of lead and cadmium were measured to the third decimal place
 (0.001mg/dl), and concentrations below that were considered to be zero.
 <strong>Statistical
 analyses</strong> The
 continuous variables are presented as means ± standard deviation. The
 categorical variables are presented as the number of cases and
 percentages. An independent t-test was used to evaluate the significance
 of the mean differences between the continuous variables for demographical
 factors such as age and body mass index (BMI). The Cox proportional hazard
 model was used to identify potential predictors in the baseline
 characteristics for type 2 DM in subjects who were not diagnosed with DM.
 In the Cox hazard model, the development of type 2 DM was considered a
 dependent variable and as independent variables were set to the exposure
 levels of lead and cadmium and the known risk factors (age, BMI, smoking,
 drinking, HbA1c, FBS, and ferritin). A mixed model was used to assess the
 effects of heavy metal exposure and ferritin on FBS and HbA1c,
 respectively. The annual changes in FBS and HbA1c with lead concentrations
 are shown in a scatter plot. Stata 14.0 software (Stata Corporation,
 College Station, TX, USA) was used for all statistical
 analyses.
 <strong>Operational definitions</strong>
 1. Type 2 DM was
 defined in patients with a diabetes diagnosis history taking anti-diabetic
 medication or satisfying the American Diabetes Association (ADA) criteria
 of HbA1c ≥ 6.5% or FBS ≥ 126 mg/dl in a blood test after an 8-hour fast.
 2. Newly diagnosed diabetes was defined in
 subjects without a history of diabetes who had an HbA1c of &lt; 6.5%
 and an FBS of &lt; 100 mg/dl in the first health check-up after
 joining the company and were newly diagnosed with diabetes (HbA1c ≥ 6.5%
 or FBS ≥ 126 mg/dl) in a follow-up health check-up conducted at least one
 year later. 
 3. The heavy metal
 exposure subjects were those who worked in the lead industry, those who
 were in charge of lead welding and mounting in shipyards, and subjects who
 worked in Ni-Cd battery manufacturing
 factories.
 4. Simple
 occupational exposure to lead or cadmium, called simple exposure, referred
 to subjects who worked on-site at the workplace regardless of the
 intensity of the
 exposure.
 5. The beginning of
 exposure referred to the first occupational health examination conducted
 within a year of working in the workplace related to heavy metal
 exposure.
 <strong>Patient and public
 involvement</strong> The
 patients and the public were not involved in the development of the
 research question or the design of the study. No patients or public
 members were involved in the recruitment or conduct of the study. Since
 this study used de-identified results, the authors do not plan to
 disseminate the study results to the study participants individually but
 plan to publish the paper with open
 access.