Jonathan’S.’Rutchik,’MD,’MPH’ Associate’Professor

3/11/16

1

Chemical Toxicity to the Special Senses: Vision, Hearing, Taste, and Smell

Jonathan S. Rutchik, MD, MPH Associate Professor, Department of Medicine

Occupa=onal Medicine, UCSF Neurology, Environmental and Occupa=onal Medicine Associates

Mill Valley, CA

Introduc=on

•  50% of neurotoxic chemicals may affect some aspect of SENSORY SYSTEM. • Most sensi=ve to exposure related toxicity •  First reported following exposure. •  Exist in the absence of other organ toxicity •  Visual symptoms are the most frequently reported. •  Altera=on in structure and func=on of the eye are oHen the criteria u=lized for seJng permissible exposure limits for chemicals in the USA

•  Visual processing of informa=on can have immediate, long term, delayed effects on mental, social and physical health and performance

•  Auditory and visual impairments can lead to occupa=onal injuries.

www.neoma.com 3/10/16 2

3/11/16

2

Overview

•  Neuro-‐Ophthalmological Dysfunc=ons (Toxicology of the Visual System)

•  Ototoxicity (Toxicology of the Auditory System)

•  Gustatory Dysfunc=ons (Toxicology of the Sensory System of Taste)

•  Olfactory Dysfunc=on (Toxicology of Sensory System of Smell)


Occupa=onal Exposures

• Greater than 80,000 industrial chemicals in use today. • Approx. 3,000 chemicals known toxic to the eye/visual system. • Routes of exposure can vary depending on chemical form (i.e., fumes, liquids, solids).

•  Inhala=on (e.g., fumes, gases) – Primary route of occupa=onal exposures •  Inges=on (e.g., liquids, dust) •  Absorp=on (e.g., solvents)

• Onset of illness can be either by ACUTE or CHRONIC exposures •  Chronic exposures are the most widely studied.


3/11/16

3

Visual System Anatomy

• Peripheral •  External Layers of the Re=na

•  Color Vision (cones) •  Night vision (rods)

• Central •  Internal layers of the re=na •  Op=c Nerve •  Visual Pathways •  Visual Cortex


Visual System Dysfunc=on

• Peripheral Visual System •  Re=nal pigmented epithelium (RPE)

•  photoreceptors have highest O2 consump=on of any =ssue in the human body

•  75% of the re=nal mitochondria in this area (vulnerable to toxicity) •  High body affinity to bind PAH and metals including Pb, Hg

• Central Visual System Pathways • Op=c nerve and Visual cortex

•  increased basal oxygen consump=on increases with visual s=muli


3/11/16

4

Visual System Tes=ng

• Color Vision Tes=ng (dyschromotopsia)

•  Electrore=nogram (inner and outer layers)

• Visual Field Tes=ng (Op=c nerve dysfunc=on)

• Oculomotor Tes=ng (Cranial nerve dysfunc=on)

• Contrast Sensi=vity Tes=ng (nonspecific threshold tes=ng)

• Cri=cal Flicker Fusion (non specific)

• VISUAL SEARCH PERFORMANCE • Visual Evoked Poten=al Tes=ng (central pathway dysfunc=on)


Vision Tes=ng Methods

•  Color Vision Tes=ng •  Farnsworth-‐Munsell 100 (FM-‐100) Hue Color Vision Test •  Lanthony Desaturated D15 (LD15), or D15d most u=lized.

• Visual Evoked Poten=al (VEP) •  Ini=ated by brief visual s=muli, recorded by EEG signals. •  Measures func=onal integrity of the visual pathways from re=na via the op=c nerves to the visual cortex of the brain.


3/11/16

5

Kollner’s Rule and Dyschromatopsia •  Dysfunc=on can be localized by the type of vision loss:

•  Toxicity to peripheral system (Re=na) leads to Blue-‐Yellow (BY) deficits •  Toxicity to central pathways leads to Red-‐Green (RG) deficits

•  Type III: External re=nal layers: BY loss; RARE INHERITED, ALTITUDE? •  normal to moderate acuity loss. TRITAN

•  Type II: Internal re=nal layers: RG and BY loss ; •  moderate to severe acuity loss. DEUTAN

•  Type I: Internal re=nal layers: RG loss: •  moderate acuity loss. PROTAN


Toxins Associated with Vision Loss Occupa=onal Exposure to Styrene

Industrial solvent in the manufacturing of plas=cs; associated with altera=ons in color vision (Type III blue-‐yellow) in workers exposed to concentra=ons between 4-‐70 ppm for 5-‐17 years (Fox 2015).


3/11/16

6

Toxins Associated With Vision Loss Occupational Exposure to Perchloroethylene and Trichloroethylene

33 dry cleaners (mean age 31) exposed to occupa=onal levels of TCE Results showed significantly lower contrast sensi=vity (p <0.05) and poorer color discrimina=on (BY) when compared to controls (n = 35). High level deficits in percep=on of global form and mo=on were also recorded (p <0.0001).


Toxins Associated With Vision Loss Occupa=onal Exposure to Carbon disulfide Vast industrial uses (e.g., clothing, industrial solvent, pes=cides) Known for neurological and vascular dysfunc=on: re=nal altera=ons (e.g., retrobulbar neuri=s, pre-‐senile arteriosclero=c changes in the fundus, microaneurysms and small hemorrhages, delayed papillary filling, and irregulari=es in the caliber of re=nal arterioles and veins). Clinical studies describe severe loss of central vision (central scotoma), decreased sensi=vity in peripheral visual fields (rod scotoma), op=c atrophy, blurred vision, impaired color vision (BY), and papillary changes.


3/11/16

7

Toxins Associated With Vision Loss Occupa=onal exposure to Lead (Pb) – inorganic Lead-‐acid banery manufacturing, welding, electronic manufacturing (lead solder), jewelry making, etc. Decreases in cri=cal flicker fusion have been recorded in workers with a mean blood lead level (BLL) of 35-‐47 ug/dL. Peripheral and paracentral scotomas have also been seen in workers chronically exposed (>5 yrs) to moderate-‐levels of Pb or those acutely exposed to high-‐levels of Pb. Many papers prior to 2000 documen=ng visual toxicity to lead using various method of assessment.


GENETICS AND ENVIRONMENT

• Macular degenera=on •  Lead may accumulate in RPE layers and has been associated. •  Herbicides in in drinking water.

• Glaucoma and hair lead.

•  Leber’s Op=c Hereditary Neuropathy and organic solvents.


3/11/16

8

Ototoxicity: Auditory system anatomy

•  Inner ear includes Cochlear hair cells •  Converts of sound waves of different frequencies and amplitudes into electrical signals

•  Tonotopically organized with different sounds s=mula=ng different areas of the organ which then s=mulate different brain stem cell nuclei and different areas of auditory cortex

•  Conduc=on hearing deficit is the outer ear (on the way to the inner ear) •  Sensory neural hearing loss is a change in the cochlea •  Central hearing loss localizes to the acous=c nerve or auditory cortex •  Outer hair cells affected first •  Cochlear hearing loss is most common due to aging and noise


Noise induced hearing loss

•  10 years or more: •  8% of 85 db; 22% of 90 db; 38% of 95 db; 44% of 100 db

•  20-‐25 db threshold shiHs, and 10 db, high frequency loss is normal •  Should not progress if noise ceases •  Early detrimental exposure leads to worsened suscep=bility to progression with age related hearing loss

•  Higher frequencies first affected than progress to lower frequencies •  Combina=on with ototoxicity and aging •  In 1940, occupa=onal popula=ons had higher prevalence of hearing loss without noise exposure in industry


3/11/16

9

Audiology Tes=ng Methods (Not sensi=ve to ototoxicity)

•  Pure-‐Tone Audiometry (R/L ear hearing sensi=vi=es)

•  High-‐Frequency Audiometry (Frequencies: 10, 12.5, 14 and 16 kHz)

•  ImmiPance Audiometry (physical volume, tympanometry, etc.)

•  Behavioral and Reflex modifica=on audiometry (animals, startle and warning thresholds)

•  Electrocochleography

•  Central Auditory Processing Test (electrophysiological and behavioral tests www.neoma.com 3/10/16 17

Toxins Associated with Hearing Loss Occupa=onal Exposure to Solvents (e.g., Styrene, Toluene, Trichloroethylene)

Plas=cs (styrene), paint industry (toluene), dry cleaning industry (trichloroethylene). Synergis=c rela=onship; exposures and to noise. Cochlear toxicity. Long-‐term exposure to Styrene ((OEL 20-‐100 ppm): demonstrated auditory effects in workers exposed to 30-‐50 ppm for at least 10 years with levels above 50 ppm in the past. In humans, the type of interac=on taking place between noise and styrene exposure is not yet clear. Ototoxic effects (BAER abnormali=es) from Toluene (OEL 20-‐200 ppm): associated with current exposure levels of approximately 10-‐50 ppm. Historic toluene and/or noise exposure levels not well characterized and some with co-‐exposures. Exposed to higher concentra=ons in past and present could explain.


3/11/16

10

Toxins Associated with Hearing Loss Occupational Exposure to Lead (Pb)

Used in gasoline as an an=knocking agent; jewelry industry, the automo=ve industry (e.g., lead-‐acid baneries), and in industrial paints. Inhala=on of dust and fumes; inges=on in children. Central auditory effects (BAER) found with currect and life =me weighted average of 28-‐57 ug/ dl of BLL.

Workers with a mean BLL of 37 ug/dL as having significant increases in hearing thresholds compared to controls.

Uncertain interac=on with noise and lead.


Hearing loss and Toxicity

•  TCE, CS2, Xylene, N hexane, Hg, CO, Pes=cides associated with auditory effects in humans.

•  Occupa=onal studies (styrene, toluene, solvent mixtures and lead) indicate that much lower levels in industrial seJngs were associated with hearing deficits.

•  Combina=ons of exposure with noise, other stressors such as physical ac=vity during exposure contribute to lower exposure intensity and dura=on leading to ototoxicity


3/11/16

11

Olfactory Toxicity and Anatomy

•  Olfactory Dysfunc=on 1-‐5% from toxins. •  Exposures irrita=on and removal natural •  Chronic exposures, subthreshold dangerous with =me; unno=ced gradual decrease of func=on.

•  Age related loss secondary to accumula=on of damage from low level non irritant exposures?

•  Olfactory epithelium direct contact (10% of respired air flow) •  Regenera=ve capacity •  Immunological defense, an=microbial agents, etc •  Metabolizing poten=al detoxifica=on (reac=ve oxygen scavenging) or increasing toxicity?

•  Neurons with dendrites extending into Cribiform plate to contact directly with olfactory bulb in CNS.

•  Gases and solvents may reach olf bulb via systemic circula=on, Metals via receptors


Olfactory Dysfunc=on

•  Types of olfactory dysfunc=on: •  Psychophysical (detec=on sensi=vity)

•  Electrophysiological (measured electrical changes following s=mulus)

•  Psychophysiological (assess odor-‐induced autonomic nervous system

responses)


3/11/16

12

Olfactory Tes=ng Method

•  UPSIT (University of Pennsylvania Smell Iden=fica=on Test)

•  Test consists of 4 different 10 page booklets with “scratch and sniff” strips

•  Scoring accounts for age and gender

•  Considered the gold standard of smell iden=fica=on

•  Used in tes=ng for a mul=ple of neurological diseases such as: Parkinson’s

disease, Alzheimer’s, Hun=ngton’s disease, brain tumors, and Mul=ple

Sclerosis


Toxins Associated With Olfactory Dysfunc=on Highlights from the literature

• Cadmium: Olfactory dysfunc=on noted even at ACGIH proposed levels.

• Mercury: UPSIT u=lized in Minimata Bay survivors and found reduced ability to iden=fy s=muli.

• Manganese: Excitability of neurons heralds toxicity, then func=on decreases. Increase in urine Mn associated with lower detec=on threshold; lower in iron alloy workers. Changes related to dopaminergic dysfunc=on at the level of receptor. Ac=ve transport through olfactory tract.

• Popula=ons in Italy with elevated environmental exposure to Mn had increased prevalence of PD and odor iden=fica=on.


3/11/16

13

Toxin Associated Olfactory Dysfunc=on

•  Lead: No influence on Olfactory system in tetraethyl lead manufacturers using UPSIT.

•  Toluene: Inhala=on chamber study revealed increased thresholds that returned to normal. No permanent insult

• Paint solvent: UPSIT tes=ng revealed dose related decrement in non smoking paint manufacture workers sugges=ng protec=on.


Gustatory Toxicology: Anatomy of Taste

Saliva contains sodium, potassium, chloride and bicarbonate Salivary glands: paro=d, submandibular, sublingual and minor

Autonomic nervous system controlled Altera=on of components or volume will affect sal=ness, sourness Autoimmune disorders, medicines, systemic diseases

Oral mucosa Chemical burns, fungi, viruses, tobacco, gastric acid

Taste Bud Receptors-‐ Ac=vated; reduced in number Botox, tetrodotoxin, chemotherapeu=cs, tobacco

Central pathways Infec=on, inflamma=on: Botox, HZV, Bells palsy, GBS, poliomyeli=s, MS


3/11/16

14

Gustatory Tes=ng Methods

•  Taste strips (taste infused strips) •  Inexpensive and very simple to use

•  Administered and recorded in clinical or field seJng) •  Electrogustometry (measurement of taste threshold)

•  Clinical seJng

•  Pass controlled anodal current through the tongue causing unique and dis=nct metallic taste (e.g., sensa=on experienced when placing 9-‐volt banery

on the tongue)


Toxins Associated with Gustatory Dysfunc=on Isodecanes used in manufacturing of paint, imaging toners and floor cleaners.

•  63-‐year-‐old woman: Smell and taste loss aHer a 3-‐year exposure. Ini=ally welts on her tongue and lips, chest =ghtness, biner taste 8 years prior.

•  Gradual smell and taste loss, intraoral burning sensa=ons, and periodic perioral derma==s.

•  No improvement occurred with cromolyn sodium, zinc chloride, or copper sulfate.

•  Examina=on of the olfactory epithelium revealed a flat, yellow area with scarring. Sinus CT scan was normal.

•  Olfactory tes=ng: mild-‐to-‐moderate hyposmia. •  Suprathreshold taste tes=ng: Depressed intensity ra=ngs, poor taste iden=fica=on, and no response to biner s=muli.

•  AHer topical anesthesia, taste responses were reduced to zero. •  Ineffec=ve treatment.


3/11/16

15

Toxins Associated with Gustatory Dysfunc=on Acute ammonia exposure

• A 31-‐year-‐old man presented with hypogeusia 4 months aHer bi=ng down on an ammonia capsule hidden in a store-‐bought sandwich.

• He sustained an intraoral chemical burn injury, immediate-‐onset ageusia, and decreased sensi=vity to oral s=muli.

• His medical history was significant for environmental allergies. He smoked <1 pack of cigarenes per day for <5 years.

•  Examina=on and olfactory tes=ng was normal. •  Suprathreshold taste was consistent with hypogeusia: iden=fied s=muli of moderate and high concentra=on.


Toxins Associated with Gustatory Dysfunc=on Lead (Pb)

• Workers complain of metallic tastes, coinciding with a specific metal. • Brass pipe finers and jewelry workers suffering from lead poisoning, frequently report a persistent, sweet, metallic taste.

• Because heavy metals are concentrated in saliva and their topical applica=on on the tongue can diminish taste percep=on, a possible direct mechanism of ac=on has been hypothesized


3/11/16

16

Toxins Associated with Gustatory Dysfunc=on Occupa=onal exposure to Chromium (Cr)

• Metal plaJng, an=-‐corrosive agent, manufacture of stainless steel

•  Increased taste thresholds noted in workers with chromium

exposures using both chemical s=muli and electrical s=muli.


Toxins Associated with Gustatory Dysfunc=on Organophosphate-‐based pes=cides (e.g., DDT, Parathion)

• Workers with frequent exposure to pes=cides have complaints of sustained metallic, biner taste.

•  Specific OP exposures associated with a garlic taste and odor. •  Experimental models, disrup=on of sensory nerve termina=ons, but they may also interfere with central neurotransminers.


3/11/16

17

Toxins Associated with Gustatory Dysfunc=on Solvents Cross-‐sec=onal study of 264 workers exposed to organic solvents Increase prevalence of smell and/or taste dysfunc=ons, similar to work related dizziness. Disturbances in smell or taste were most oHen hyposmia, but hypogeusia and a persistent “glue” taste were reported. Symptoms, however, were generally transitory, reversible, and likely due to to concentra=on peaks rather than long-‐term exposures.


Solvent-‐induced sensory dysfunc=ons Chemical Reference

Neurotoxic Sensory Endpoint(s)

Vision C or P Hearing Smell Taste

Ammonia Prudhomme et al. 1998 X

Carbon disulfide Fox D. 2015, Gobba 2003 C, P X X

Isodecanes Smith et al. 2009 X

Methyl isobutyl ketone (MIBK) Gagnon et al. 1994 X

N-‐ Hexane Gobba, 2003 P, C X

Perchloroethylene (PCE) Gobba and Cavalleri 2003 P., C

Styrene Fox D. 2015; Kjell, ed. 2010 P X

Toluene Fox D. 2015; Kjell, ed. 2010, Mergler 1992 P, C X X

Trichloroethylene (TCE) Barbosa et al. 2015, Gobba 2003 P, C X X

Xylene Gobba 2003 X X


3/11/16

18

Heavy metal-‐induced sensory dysfunc=on

Chemical Reference Neurotoxic Sensory Endpoint(s)

Vision, C or P Hearing Smell Taste

Arsenic Gobba 2006, 2003 X X

Cadmium Mascagni, 2003, Gobba 2003 X X X

Chromium (Cr) Reiter et al. 2006; Seeber et al. 1990, Gobba 2003 X X

Lead (Pb) Fox D. 2015; Kjell, ed. 2010; Reiter et al. 2006; Bolla et al. 1995 C X X X

Manganese (Mn) Antunes et al. 2007; Bowler et al.; Zoni et al. 2012, Sinczuk-‐ Walzak 2001 X X X

Mercury (Hg) Gobba 2006, 2003 Organic C, Inorg C,

Elemental P X X X


Pes=cide-‐induced sensory dysfunc=on

Chemical Reference Neurotoxic Sensory Endpoint(s)

Vision Hearing Smell Taste

Chlorpyrifos Gobba, 2003. X

DDT Reiter et al. 2006 X

OP-‐based pes=cides Reiter et al. 2006 X

Parathion Reiter et al. 2006 X

Sulfuryl fluoride Calvert et al. 1998 X


3/11/16

19

References •  Antunes MB, Bowler RM, Doty RL. San Francisco/Oakland Bay Bridge welder study: olfactory func=on. Neurology 2007;69:1278–84.

•  Barbosa IAJ, Boon MY, Khuu SK (2015). Exposure to Organic Solvents Used in Dry Cleaning Reduces Low and High Level Visual Func=on. PLoS ONE 10(5):e0121422. Doi:10.137/journal.pone.0121422.

•  Bolla KI, Schwartz BS, Stewart W, Rignani J, Agnew J, Ford DP. Comparison of neurobehavioral func=on in workers exposed to a mixture of organic and inorganic lead and in workers exposed to solvents. Am J Ind Med 1995;27(2):231–46.

•  Bowler RM, Gocheva V, Harris M, et al. Prospec=ve study on neurotoxic effects in manganese-‐exposed bridge construc=on welders. NeuroToxicol. 2011;32:596-‐605.

•  Erie JC, Good JA, Butz JA. Excess lead in the neural re=na in age-‐related macular degenera=on. Am J Ophthalmol. 2009;148:890–894.

•  Farahat TM, Abdel-‐Rasoul GM, El-‐Assy AR, Kandil SH, Kabil MK. Hearing thresholds of workers in a prin=ng facility. Environ Res. 1997;73:189–92.

•  Fox D. (2015). Re=nal and visual system: occupa=onal and environmental toxicology. In. LoJ M and Bleecker ML (Eds). Handbook of Clinical Neurology, Vol. 131 (3rd Series) OccupaJonal Neurology. (pp 325-‐340). Elservier BV.

•  Frank ME, HeJnger TP. What the Tongue Tells the Brain about Taste. Chem. Senses. 2005;30(Supp 1): i68-‐i69. www.neoma.com 3/10/16 37

References (cont’d)

•  Furuta S, Nishimoto K, Egwa M, Ohyama M, Moriyama H. Olfactory dysfunc=on in pa=ents with Minimata disease. Am J Rhinol 1994;8:259–63

•  Gobba F, Cavalleri A. Color Vision Impairment in Workers Exposed to Neurotoxic Chemicals. NeuroToxicology. 2003;24:693-‐702.

•  Gobba F. Olfactory toxicity: long-‐term effects of occupa=onal exposures. Int Arch Occup Environ Health. 2006;79:322-‐331.

•  Hotz P, Tschopp A, Söderström D, et al. Smell or taste disturbances, neurological symptoms, and hydrocarbon exposure. Intl Arch Occupa Environ Health. 1992;63(8):525-‐530.

•  Johns DR, Smith KH, Miller NR (1992). Leber’s hereditary Op=c neuropathy. Clinical manifesta=ons of the 3460 •  Johnson and Morata, Occupa=onal Exposures to Chemical and Hearing Impairment. In Torén Kjell, Editor-‐in-‐Chief.

Arbete och Hälsa (Work and Health). Occupa=onal and Environmental Medicine at Sahlgrenska Academy, Univ. of Gothenburg. 2010.

•  Klein BE, McElroy JA, Klein R et al. Nitrate-‐nitrogen levels in rural drinking water: is there an associa=on with age-‐related macular degenera=on? J Environ Sci Health A Tox Hazard Subst Environ Eng. 2013;48:1757–1763.

•  LoJ M and Bleecker ML, editors. Handbook of Clinical Neurology, Vol. 131 (3rd Series) Occupa=onal Neurology. Elservier BV. 2015.


3/11/16

20

References (cont’d) •  Mascagni P, Consonni D, Bregante G, Chiappino G, Toffoleno F. Olfactory func=on in workers exposed to moderate airborne cadmium levels. Neurotoxicology 2003;24(4–5):717–24.

•  Mergler D, Beauvais B. Olfactory threshold shiH following controlled 7-‐h exposure to toluene and/or xylene. NeuroToxicol. 1992;13(1):211–15.

•  Morata TC, Fiorini AC, Fischer FM, Colacioppo S, Wallingford KM, Krieg EF, Dunn DE, Gozzoli L, Padrao MA, Cesar CL. Toluene-‐induced hearing loss among rotogravure prin=ng workers. Scand J Work Environ Health 1997b;23(4):289–98.

•  Prudhomme, JC, Shusterman DJ and Blanc PB. Acute-‐Onset Persistent Olfactory Deficit Resul=ng From Mul=ple Overexposures to Ammonia Vapor at Work JABFP Jan.-‐Feb.I998 Vol. II No.1

•  Reiter ER, DiNardo LJ, Costanzo, RM. (2006). Toxic Effects on Gustatory Func=on. In, Hummel T and Welge-‐Lüssen A (Eds), Taste and Smell. An Update. Adv Otorhinolaryngol, Vol 63. (pp 265–277). Basel, Karger.

3/10/16 www.neoma.com 39

References

•  Schwartz BS, Ford DP, Bolla KI, Agnew J, Rothman N, Bleecker ML. Solvent-‐associated decrements in olfactory func=on in paint manufacturing workers. Am J Ind Med. 1990;18(6): 697–706.

•  Sinczuk-‐Walczak H, Jakubowski M, Matczak W. Neurological and neurophysiological examina=ons of workers occupa=onally exposed to manganese. Int J Occup Med Environ Health 2001;14(4):329–37.

•  Smith WM et al. Toxin-‐induced chemosensory dysfunc=on: A case series and Review. Am J Rhinol Allergy. 2009 ; 23(6): 578–581.

•  Treibig et al. Occupa=onal Styrene exposure to and hearing loss. Int Archives of Occupa=onal and Environmental Health 2009; 82; 463-‐480

•  Upadhyay UD et al. Olfactory loss as a result of toxic exposure. Otolaryngol Clin N Am 37 (2004) 1185–1207 2004

•  Yuki K, Dogru M, Imamura Y, et al. Lead accumula=on as possible risk factor for primary open-‐angle glaucoma. Biol Trace Elem Res. 2009;132:1–8.


3/11/16

21

MOC Ques=on ONE

• Which industries have NOT been studied regarding color vision toxicity?

• A. Dry cleaning • B. Airline workers • C. Boat builders • D. Tetraethyl Lead workers


MOC Ques=on TWO

• Which of these sensory systems anatomical areas are considered part of the Central Nervous System?

• A. Olfactory Bulb • B. Cribiform Plate • C. Salivary Glands • D. External Re=nal Layer


3/11/16

22

MOC Ques=on THREE • Which neurophysiological test is matched incorrectly? • A. Cri=cal Flicker Fusion: Vision • B. UPSIT: Smell • C. Electrogustography: Taste • D. High Frequency Audiometry: Hearing •  E. None


Answers

•  I. B •  II. A •  III. A-‐3,B-‐1,C-‐2, D-‐4


Documents

Jonathan’S.’Rutchik,’MD,’MPH’ Associate’Professor