2/27/2017 WHAT’S NEW IN HAZARDOUS NOTHING TO DISCLOSE TECHNOLOGIES AND EXPOSURES? GINA M. SOLOMON, M.D., M.P.H. DEPUTY SECRETARY FOR SCIENCE AND HEALTH, CALEPA CLINICAL PROFESSOR OF MEDICINE, UCSF 3-D PRINTERS OUTLINE • New Technologies with Potential Hazards Fused Filament Fabrication • Acrylonitrile butadiene styrene • 3-D printing (ABS) • Laser cutting and engraving • Polylactic acid (PLA) • Fluorinated telomeres • Polyvinyl alcohol (PVA) • Polycarbonate • New Exposure Concerns • High-density polyethylene (HDPE) • Preservatives: MI/MCI • High-impact polystyrene (HIPS) • New Tools in Toxicology and Exposure Science • Nylon, and other polymers • Metals Starting at • Pathway-based toxicology $699 • Ceramics • Sensor air monitoring technologies • Other 1
2/27/2017 VOC EMISSIONS: 3D PRINTERS PARTICULATE EMISSIONS: 3D PRINTERS • Caprolactam from nylon-based and imitation wood and brick filaments ( ∼ 2 to ∼ 180 μ g/min) • Styrene from ABS plastics and from high-impact polystyrene (HIPS) filaments ( ∼ 10 to ∼ 110 μ g/min) • Lactide from polylactic acid (PLA) filaments ( ∼ 4 to ∼ 5 μ g/min) Azimi et al. ES&T, 50:1260, 2016 Kim et al. ES&T, 49:12044, 2015 2
2/27/2017 FLUORINATED TELOMERS LASER ENGRAVING OR CUTTING • Perfluoroalkyl substances (PFASs) Laser-Generated Air Contaminants (LGACs) Types of Lasers • Include PFOA and PFOS (no longer used in the U.S.) • Polycarbonate: Cresol • Fiber lasers • PVC: Chlorine gas, HCL, phosgene • Used in greaseproof, waterproof, stain-repellant • CO2 lasers • PET: Tetrahydrofuran (THF) coatings; aqueous fire fighting foams (AFFFs) • Nd and Nd-YAG • Epoxy: Isocyanates, amines • Rubber: 1,3-Butadiene • Mild steel: Iron oxide, NO, NO2, CO • Stainless steel: nickel, chromium • Carbon monoxide Medical laser contaminants reported: Carbon monoxide, hydrogen sulfide, ammonia, toluene, styrene, phenol, benzyl cyanide, and hydrocyanic acid. PERFLUOROALKYL SUBSTANCES CASE REPORT • 42 families and subfamilies of PFASs and at least • A 36-year-old previously healthy woman was sent to 268 individual PFASs – Chain length is important • Only PFOA and PFOS are well-studied the ER by her PMD for suspected pneumonia. She was a smoker and worked as a secretary. Her sxs included • Environmentally persistent; Detectable in biota acute onset of dyspnea, dry cough, a fever of 103 ˚ F, • Highly water soluble generalized muscle aches, headache, nausea and • Found in most house dust samples vomiting. • Some PFASs present in serum of almost all people • PE respiratory rate of 22, O 2 sat of 89%. Obvious sampled dyspnea, lungs clear to auscultation. Calafat et al. Environ Health Perspect 2007, 115:1596, 2007. 3
2/27/2017 “WERE YOU EXPOSED TO ANY CHEMICALS?” “HILL WALKERS LUNG” • Acute alveolitis or interstitial pneumonitis after acute inhalation of water • ~1 hour prior to onset of symptoms, she sprayed her shoes repellant sprays; distinct from polymer fume fever. with a waterproofing spray. She used it indoors with the • Contents of the sprays: Propellants (propane, butane, isooctane) and water windows closed and without PPE. She had used it similarly in repellant (fluorocarbons, silicone resins) the past without any apparent adverse effects. • Dyspnea, dry cough and an acute febrile and flu-like disease • Disrupts alveolar surface tension and surfactant -- alveolar collapse? In animals causes necrosis of alveolar cells, alveolar hemorrhage and edema. Epping et al. Int J Occup Med Environ Health. 2011, 24(4):409-13 OTHER HEALTH EFFECTS OF PFOA AND PFOS PRESERVATIVES: MCI AND MI • Methylchloroisothiazolinone (MCI) and methylisothiazolinone (MI) • In humans: • Introduced for industrial use in 1980 • Immune alterations, low birth weight, decreased head circumference, reduced birth • Approved by the FDA in 2005 (max conc. 100 ppm) length, and smaller abdominal circumference • Associations with testicular and kidney cancer. • Now in >1000 products: baby lotions, bath products, makeup, • In animals: hair care products, deodorants, skin care products, sunscreens • Developmental toxicity, changes in brain function and behavior, altered mammary gland • First case reports of sensitization in 2011 development, immune system effects, altered weight gain after in-utero exposure, thyroid hormone disruption, and reduced testosterone. • Increased incidence of tumors of the liver, testes, and pancreas. Grandjean et al. Environmental Health 2013, 12:35. http://biomonitoring.ca.gov/chemicals/perfluorochemicals-pfcs 4
2/27/2017 CONTACT DERMATITIS • Prevalence of contact allergy to MI increased from 2.5% in 2012 to 6.8% in 2014 • Combined frequency of allergy to MI/MCI is 11.1% • Sources: Cosmetics, soaps & cleansers, hair care products; water-based paints; rarely occupational • European Commission banned MCI-MI in leave-on body products - July 2015 • No restrictions in the U.S. Yu et al. JAMA Dermatol. 2016;152(1):67 HIGH-THROUGHPUT SCREENING ASSAYS COMPETING NEEDS FOR MODERN TOXICOLOGY Batch testing of chemicals for pharmacological/toxicological endpoints using automated liquid handling, detectors, and data acquisition LTS MTS HTS uHTS Test more chemicals Test more quickly National Academies Press, 2007 Gene-expression 1000s/day Use fewer lab animals 10s-100s/yr Test more life stages 10,000s- 100,000s/day 10s-100s/day Test for more endpoints Test more cheaply Human Relevance/ (endocrine, Cost/Complexity neurotox, immuno) Throughput/ 20 Simplicity 5
2/27/2017 TOXCAST IN VITRO HTS ASSAYS Assays Biochemical Assays Cellular Assays ( n = 467) • • Protein families Cell lines • HepG2 human hepatoblastoma • GPCR • A549 human lung carcinoma • NR • HEK 293 human embryonic kidney • Kinase • • Phosphatase Primary cells • Human endothelial cells • Protease • Human monocytes • Other enzyme • Human keratinocytes Chemicals ( n = 320) • • Ion channel Human fibroblasts • Human proximal tubule kidney cells • Transporter • Human small airway epithelial cells • • Biotransformation competent cells Assay formats • Primary rat hepatocytes • Radioligand binding • Primary human hepatocytes • Enzyme activity • • Co-activator recruitment Assay formats • Cytotoxicity • Reporter gene • Gene expression • Biomarker production • High-content imaging for cellular phenotype Judson et al EHP (2010) http://www.epa.gov/ncct/toxcast/ 11 Using the Data: Overall Biological Activity EXAMPLE: SIGNATURE DERIVATION FOR LIVER CARCINOGENS TR .assay .hit.percentage ER .assay .hit.percentage Other.assay .hit.percentage AR .assay .hit.percentage Lipinski_LS.norm alized endpoint.hit.count.percentage Ingenuity .pathway .hit.percentage KEGG.pathway .hit.percentage Bisphenol A Fenitrothion Perfluorooctane Linuron Symclosene sulfonic acid 24 12 6
2/27/2017 >9,000 chemicals; >1,000 assays https://actor.epa.gov/dashboard/ Contains: Chemical structures, https://comptox.epa.gov/dashboard experimental and predicted physicochemical and toxicity data, and additional links AIR SENSORS, A RAPIDLY GROWING TECHNOLOGY DATABASE RESOURCES ON CHEMICALS • ToxCast and Tox21 - High-throughput chemical screening data • ExpoCast - Chemical exposure data and prediction models • DSSTox - High quality chemical structures and annotations • PhysChemDB - Physical Chemical Properties Database • CPCat - Chemicals listed by associated categories of chemical and product use https://www.epa.gov/chemical-research 7
2/27/2017 US EPA VILLAGE GREEN AND AIRMAPPER Neighborhood Monitor with Real-Time Data and Web Dashboards AirMapper, a real-time particle instrument for measuring personal exposure CAIRCLIP: REAL-TIME, HAND-HELD OZONE AND NO 2 U.S. EPA “MY AIR, MY HEALTH” CHALLENGE • Sensor system that detects air pollutants and physiological markers with a known or plausible link to air pollution TZOA – ENVIRONMENTAL TRACKER • Winner “Conscious Clothing” • Measures: • Particulate matter • Tidal volume • Breathing rate https://www.innocentive.com/ar/challenge/9932947 8
2/27/2017 Crowd Sourcing REAL-TIME IAQ MONITORING • Folding@Home • Habitatmap/Aircasting • Stanford project to • Platform for mapping and understand protein folding sharing environmental data by crowd sourcing using your smartphone computation Aclima 2016: https://aclima.io/blog/posts/how-ventilation-indoor-temperature-and-carbon-dioxide-are-linked/ A 37 yo woman presents with recent onset of a rash on her face A 23 yo male presents with new onset of cough and and hands. The rash is shown below. Which of the following is most dyspnea. His exam is notable for scattered wheezes but likely associated with the rash? he appears otherwise healthy. Relevant considerations include all of the following except: 1. Styrene from an ABS cartridge on a 3-D printer 1. Was he exposed to a 3-D printer, laser cutter, or engraver? 2. Caprolactam from a nylon filament on a 3-D printer 2. Did he recently use a waterproofing spray? 3. Laser cutting on PVC plastic releasing phosgene 3. Is he using a new shampoo or soap? 4. A preservative in her soap 4. Is anyone else at work or at home having similar symptoms? 9
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