Disclosures: None Key Publications in OEM Exposure to - PDF document

Key Publications in Occupational & Environmental Health: the Year in Review Samuel M. Goldman, MD, MPH Professor of Clinical Medicine UCSF Division of Occupational & Environmental Medicine Disclosures: None Key Publications in OEM  Exposure to disinfectants in health care workers has been associated with asthma  Very little data on associations with COPD Key Publications in OEM

Methods  Nurses Health Study II prospective cohort, 1989-forward  Women in 14 states, aged 25-44 (n=116,249)  Questionnaire every 2 years  Present study: - Still in nursing job and free of COPD in 2009 (year of first occupational exposure hx) - Questionnaire data from 2009-2015 - Exposure: a) questionnaire, b) job-task-exposure matrix (JTEM) - Outcome: self-reported physician-diagnosed COPD, emphysema, chronic bronchitis; validated in subset Key Publications in OEM Exposure Assessment & Analysis  Nursing job type  Disinfection tasks (none/surfaces/instruments, sprays, frequency)  7 most common chemicals assessed by JTEM  Cox regression proportional hazards models  Highest occupational exposure level at any timepoint, time-varying  Stratified by age & calendar year  Adjusted for race, smoking (non, ex, current & packyears), BMI  Sensitivity analyses: diet (Healthy Eating Index); exclude CV disease, cancer; smoking/asthma status; interactions; stringent COPD definition Key Publications in OEM Results: baseline  N=73,262, 96% white  Mean baseline age 54.7 (4.6)  Most covariates similar across exposure groups  Slightly more smoking in “instruments” group Key Publications in OEM

Results Any Spray Job type Adjusted HR Education/admin 1 (ref) Outpatient 1.03 (0.81-1.32) ED or inpatient 1.24 (0.95-1.62 Clean Surfaces Clean Instruments OR 1.38 (0.96-1.99) Similar results in smokers & non-smokers Key Publications in OEM Results: specific chemicals Key Publications in OEM Discussion  > Weekly use of disinfectants associated with 35% increased risk of COPD  Dose response with frequency of use  surface/instrument/spray risks similar; OR jobs have highest risk  Risk highest for bleach, lowest for enzymatic chemicals  Strengths: large, longitudinal, JTEM, dose response  Limitations: - COPD definition self-reported, but….prior & current validation studies found good agreement - No PPE info - Complete/cumulative exposure data not collected - Healthy worker effect? Key Publications in OEM

 Artisanal & Small-Scale Gold Mining (ASGM) accounts for 20% of the world’s gold  The biggest source of mercury pollution in the world (~40%)  Markedly increased informal sector parallels price of gold Key Publications in OEM  Amalgamation of gold and mercury since Roman times  Major economic opportunity: ~0.5 gram per day (~$50/gram)  > 16 million workers predominantly in Asia, Africa, South America  5 million women and children  15:1 Hg:Au, 60% released to atmosphere Key Publications in OEM Whole Ore Amalgamation  https://www.youtube.com/watch?v=u6Fv6zs46A8 Key Publications in OEM

Elemental Mercury Toxicity  Route: inhalation >> dermal >> GI  Acute: - Pulmonary: pneumonitis, cough, dyspnea - CNS: headache, weakness  Chronic (“battery refiner’s disease): - Freely crosses placenta: teratogenic (CNS, renal) - Pulmonary fibrosis - CNS: fatigue, tremor, emotional lability, psychosis, myoclonus, ataxia - Renal: tubular necrosis, nephrotic syndrome - Enteritis, sialorrhea, gingivitis - Acrodynia (small children, pink disease): rash, extremity edema, desquamation, photophobia, profuse sweating Key Publications in OEM  Minamata Convention of 2013 - National action plans to reduce sources of mercury - 114 parties, 41 signatories - Encourages legalization  Strategies - Improve Hg recovery - Pre-amalgamation ore concentrating - Gravimetric sluices - Hg-free approaches: direct smelting  Modest upfront investment required! Key Publications in OEM  Automotive assembly plant closures are often unexpected (to workers), discrete, and both culturally and economically significant events.  This provides a unique opportunity to estimate the consequences of an acute sustained decline in economic opportunities. Key Publications in OEM

Background  Over the past 2 decades US deaths from opiates have surged  Policy responses largely focused on supply-side factors  Erosion of economic opportunity also likely drives demand  Studies examining opioid associations with unemployment and income are inconsistent Key Publications in OEM Methods  Study period 1999-2016 All automotive plants as of 1999, location &  date of closure, if any  Identified all counties within commute distance  Restricted to commuting zones in top quintile of manufacturing job proportion (n=30 zones, 112 counties)  Individual-level death-certificate data  ICD-10 underlying & contributing cause codes  Outcome: Annual county-level age-adjusted death rates from opioid overdose, ages 18-65  Analyses adjusted for county-level fixed effects (e.g. rurality, SES) & calendar year Key Publications in OEM Baseline Characteristics • 10 commuting zones (29 counties) with closure • 20 commuting zones (83 counties) without closure • Baseline overdose mortality in 2001, immediately preceding the first auto plant closure • Other variables from 2000 US Census Key Publications in OEM

Results Opioid mortality Unadjusted trends in opioid overdose mortality difference overall by time since closure Prescription opioid mortality difference 5 years post-closure, opioid mortality Illicit opioid had increased 85% relative to counties mortality difference without a closure Key Publications in OEM • Opioid mortality differences by age & sex • Biggest impact by far seen in white men aged 18-34 • Differences in non- whites were smaller, but imprecise Key Publications in OEM Summary  5 years after an auto plant closing, deaths from opiate overdose increased 85%  Limitations: residual county-level confounding; mediators?  Illustrates importance of declining Solutions: economic activity to opiate crisis  Short-term: community-based  Structural changes to the US interventions & treatment economy associated with increasing mortality among less-  Long-term: social policies to mitigate educated adults since 1980s disparities in economic opportunity Key Publications in OEM

 36 million with Alzheimer’s  10 million with Parkinson’s  Both to double in 20 years  Genetic causes explain < 40% of AD, < 10% of PD  Mendelian variants have incomplete penetrance and variable age at onset  Identified environmental factors explain only a small fraction of risk Key Publications in OEM Neurologic Associations with Pollution  Proximity (50m) to major roads associated with 12% higher dementia risk (Chen et al, Lancet, 2017)  -amyloid in 38-year old  Urban pollution in China and US associated with cognitive decline and white matter loss (Zhang et al, PNAS, 2018; Cacciottolo et al, Translat Psych, 2017; Chen et al, Ann Neurol, 2015) Mouse exposure to concentrated ultrafine  particles causes persistent glial activation, excitotoxicity, behavioral deficits (Allen et al, Toxicol  -synuclein Sci, 2014) in 3-year old  Mexico City autopsy series found amyloid and synuclein pathology in children, middle age (Calderon-Garciduenas, Environ Res, 2018) Key Publications in OEM Ultrafines & the CNS  Ultrafines (nanoparticles) defined as < 100nm in diameter (0.1 microns) Fullerton, CA 1996  Comprise the greatest number of airborne particles, but have little mass Road traffic contributes 90% of urban ultrafines  Freely enter circulation through alveoli  Cass, et al, 2000, Phil. Trans. R. Soc. Lond Freely enter the brain through olfactory &  trigeminal nerves FeO in mouse olfactory bulb Ultrafine ZnO in rat cortex after inhalation Kao, et al, 2012, J Mol Neurosci Hopkins, et al, 2017, Toxicol Path Key Publications in OEM

Magnetite  An iron oxide (Fe 3 O 4 ) and naturally occurring rock ore  First described in human brain by Kirschvank, PNAS, 1992: 5 million crystals per gram - thought to form endogenously, as in bacteria  35% of roadside ultrafines  Also from powerplants, incinerators, biomass burning Occupational: welding, machining,  driving, printers Magnetite in roadside Magnetite-like particles magnetically samples from extracted from human brain in Mexico Birmingham, UK City & Manchester, UK Key Publications in OEM Iron & Neurodegeneration  Excess free iron (non-ferritin) is toxic to cells - Pro-oxidant: - Damage to membranes, proteins, DNA  Iron dysregulation in PD & AD - PD iron dysregulation well characterized: increased free iron in substantia nigra MRI of iron in PD brain - AD: iron associated with increased APP Ward et al, Lancet Neurol, 2014 expression Key Publications in OEM Iron oxide nanoparticles in AD amyloid plaques Transmission electron microscopy of Mapping of associated elements by nanoparticles in amyloid plaque energy dispersive X-ray analysis Key Publications in OEM