2/27/2017

WHAT’S NEW IN HAZARDOUS TECHNOLOGIES AND NOTHING TO DISCLOSE EXPOSURES?

GINA M. SOLOMON, M.D., M.P.H. DEPUTY SECRETARY FOR SCIENCE AND HEALTH, CALEPA CLINICAL PROFESSOR OF MEDICINE, UCSF

OUTLINE 3-D PRINTERS • New Technologies with Potential Hazards Fused Filament Fabrication • Acrylonitrile butadiene styrene • 3-D printing (ABS) • Laser cutting and engraving • (PLA) • Fluorinated telomeres • Polyvinyl alcohol (PVA) • • New Exposure Concerns • High-density • Preservatives: MI/MCI (HDPE) • High-impact (HIPS) • New Tools in Toxicology and Exposure Science • , and other polymers • Metals Starting at • Pathway-based toxicology • Ceramics $699 • Sensor air monitoring technologies • Other

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VOC EMISSIONS: 3D PRINTERS PARTICULATE EMISSIONS: 3D PRINTERS • Caprolactam from nylon-based and imitation wood and brick filaments (∼2 to ∼180 μg/min) • Styrene from ABS and from high-impact polystyrene (HIPS) filaments (∼10 to ∼110 μg/min) • Lactide from polylactic acid (PLA) filaments (∼4 to ∼5 μg/min)

Azimi et al. ES&T, 50:1260, 2016 Kim et al. ES&T, 49:12044, 2015

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FLUORINATED TELOMERS LASER ENGRAVING OR CUTTING • Perfluoroalkyl substances (PFASs) Laser-Generated Air Contaminants (LGACs) Types of Lasers • Polycarbonate: Cresol • Include PFOA and PFOS (no longer used in the U.S.) • Fiber lasers • PVC: Chlorine gas, HCL, phosgene • CO2 lasers • Used in greaseproof, waterproof, stain-repellant • PET: Tetrahydrofuran (THF) • Nd and Nd-YAG coatings; aqueous fire fighting foams (AFFFs) • 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 268 individual PFASs – Chain length is important • A 36-year-old previously healthy woman was sent to • Only PFOA and PFOS are well-studied the ER by her PMD for suspected pneumonia. She was • Environmentally persistent; Detectable in biota a smoker and worked as a secretary. Her sxs included • Highly water soluble acute onset of dyspnea, dry cough, a fever of 103˚ F, generalized muscle aches, headache, nausea and • Found in most house dust samples vomiting. • Some PFASs present in serum of almost all people sampled • PE respiratory rate of 22, O2 sat of 89%. Obvious dyspnea, lungs clear to auscultation.

Calafat et al. Environ Health Perspect 2007, 115:1596, 2007.

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“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 windows closed and without PPE. She had used it similarly in • Contents of the sprays: Propellants (propane, butane, isooctane) and water 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: • Immune alterations, low birth weight, decreased head circumference, reduced birth • Introduced for industrial use in 1980 length, and smaller abdominal circumference • Approved by the FDA in 2005 (max conc. 100 ppm) • 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

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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 Batch testing of chemicals for pharmacological/toxicological endpoints FOR MODERN TOXICOLOGY using automated liquid handling, detectors, and data acquisition

LTSMTS 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

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TOXCAST IN VITRO HTS ASSAYS

Assays Cellular Assays Biochemical Assays (n = 467) • Cell lines • Protein families • HepG2 human hepatoblastoma • GPCR • A549 human lung carcinoma • NR • HEK 293 human embryonic kidney • Kinase • Primary cells • Phosphatase • Human endothelial cells • Protease • Human monocytes • Other enzyme • Human keratinocytes • Human fibroblasts • Ion channel • Human proximal tubule kidney cells • Transporter = 320) • Human small airway epithelial cells n ( Chemicals

• Biotransformation competent cells • Assay formats • Primary rat hepatocytes • Radioligand binding • Primary human hepatocytes • Enzyme activity

• Assay formats • Co-activator recruitment • 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

EXAMPLE: SIGNATURE DERIVATION FOR LIVER Using the Data: Overall Biological Activity

TR.assay .hit.percentage ER.assay .hit.percentage

Other.assay .hit.percentage AR.assay .hit.percentage

Lipinski_LS.normalized endpoint.hit.count.percentage

Ingenuity .pathway .hit.percentage KEGG.pathway .hit.percentage Fenitrothion

Perfluorooctane Symclosene Linuron sulfonic acid

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>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

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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 U.S. EPA “MY AIR, MY HEALTH” CHALLENGE OZONE AND NO2

• 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

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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 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?

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An employer comes to you asking for help because his employees are complaining of headaches, fatigue, and “brain fog” in the office. Absenteeism is high. Workers have asked about air monitoring. You can tell him: 1. Indoor CO2 monitoring is not recommended because it is not associated with any of the symptoms that are being reported. 2. There are sensors that continuously monitor for temperature, humidity, PM, and CO2, and this information could help address the concerns. 3. He should hire a professional to test for benzene and formaldehyde, which could be causing these symptoms. 4. The employees are likely just malingering.

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