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ACMT Board Review

Miscellaneous Toxicants

Stephen  W.  Munday,  MD,  MPH,  MS  (Toxicology)  Medical  Toxicology  

Department  of  Occupational  Medicine  Sharp  Rees-­‐Stealy  Medical  Centers  

CPCS-­‐San  Diego  Division    

Much  appreciation  to  Brandon  Wills  for  his  previous  work  on  this  content    

Core Content – 2.2.10 Miscellaneous 2.2.10.1 Acrolein 2.2.10.2 Acrylamides 2.2.10.3 Acrylates 2.2.10.4 Amines 2.2.10.5 Aniline Compounds 2.2.10.6 Azides 2.2.10.7 Bromide Compounds 2.2.10.8 Butadienes 2.2.10.9 Carbon Disulfide 2.2.10.10 Chlorates 2.2.10.11 Coal Tar Products 2.2.10.12 Diamines 2.2.10.13 Dibromochloropropane (DBCP) 2.2.10.14 Dimethylacetamide (DMAC) 2.2.10.15 Dimethylformamide (DMF) 2.2.10.16 Dinitrobenzene 2.2.10.17 Dinitrotoluene (DNT) 2.2.10.18 Epichlorohydrin

2.2.10.19 Ethylene Dibromide (EDB) 2.2.10.20 Ethylenediamine (EDA) 2.2.10.21 Fluoride Compounds 2.2.10.22 Fuels 2.2.10.23 Hexachloro-1,3-Butadiene (HCBD) 2.2.10.24 Isocyanates (eg, toluene diisocyante) 2.2.10.25 Maleic Anhydride 2.2.10.26 Mercaptans 2.2.10.27 Methylene Diamine (MDA) 2.2.10.28 Nitriles 2.2.10.29 O-Phenylenediamine (OPD) 2.2.10.30 Phosphorus/phosphides 2.2.10.31 Phthalates 2.2.10.32 Polymers 2.2.10.33 Resins 2.2.10.34 Styrene 2.2.10.35 Trimellitic Anhydride 2.2.10.36 Triorthocresylphosphate (TOCP) 2.2.10.37 Xylidine

Our Gameplan

�  Organize your memory

�  60 min: brief review- focus on test rather than content

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Legend for this talk

U= Uses

I= Industry

T= Toxicity

M= Miscellaneous factoids

Acrolein

Acrolein = Acrid = IRRITATING

I: Contact herbicide

I: WWI Lacrimator

Acrylaldehyde, propenal, allyl aldehyde Ethylene aldehyde, aqualin, (CH2=CHCHO)

T- Water soluble irritant

T- Cellular toxin via oxygen free radicals

M- Metabolite of cyclophosphamide

Acrylamides Propenamide, acrylic amide, akrylamid

Heating Starches U- Polymer production (sodium dodecyl sulfate-polyacrymide gel electrophoresis “SDS-PAGE”), flocculator (waste-water treatment)

T-­‐  Dermatitis  (peeling,  red/blue  dermatitis:  occurs  first  and  may  be  only  finding,  hyperhidrosis  –  especially  palms  and  soles)  

T-­‐  CNS  (Delirium)  

T-­‐  Axonopathy  

 

M-­‐  Polymer  =  non-­‐toxic,  Monomer=  toxic  

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Acrylates

U- Cross-linking properties (plexiglass)

 

 

Acrylates, methylacryates, Cyanoacrylates Ethyl, methyl, 2-ethyl hexyl, butyl…

T- Irritant (skin, mucous membrane, and pulmonary)

T- Contact dermatitis (allergic or irritant)

M- Penetrates latex/ rubber easily

Amines Benzidine

Dimethylamine

Dimethylamine Trichlorotriethylamine Benzidine β-naphthylamine

-Vulcanization

AZO Dyes

Aniline Compounds

 

U- Precursor for polyurethane, indigo= blue jean die

I- Smells like rotten fish

Aniline

Aniline 4-chloroaniline 4-aminophenol Nitrobenzene 4,4’-Methylene dianiline

T- Acute: MetHb, irritant

T- Chronic: Bladder CA

Methylenedianiline: Hepatitis (Epping jaundice Due to contaminated bread) T- Aniline (Spain) Toxic oil syndrome Due to contaminated rapeseed oil (interstitial pulm dz)

Similar to eosinophilia myalgia syndrome

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Azides

U- Airbag accelerant; pesticde, explosives

I- Labs and manufacturing plants

T- Cellular asphyxiant (like CN, H2S), resp failure/ pulm edema

T- Eye irritant

Bromide Compounds

U- Photographic, hot tub chemicals, fumigants...

T- Crosses membrane faster than Cl, replacing Cl

causing sedation/ neuropsych (KBr- 19th century) [still common anti-convulsant in dogs]

T (chronic)- neuropsych, acne (30% facial), axonopathy

M- Low anion gap (false high Cl)

Butadienes

U- Monomer for plastics (ABS “Acrylonitrile-butadiene-styrene” plastic), tobacco smoke

Butadiene

1,3-butadiene Hexachloro-1,3- butadiene Many others

T- Irritant (skin and mucous membranes)

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Carbon Disulfide U- Volatile organic solvent

I- Rayon, fumigation

T- Acute: Irritant (defatting), disulfiram rxn

T- Chronic:

1. Distal axonopathy

2. Optic nerve/retinal microaneurisms

3. CV (HTN, CAD) in occupational cohorts

4. Repro (SAB, prematurity, decreased libido)

Chlorates

U- Oxidizer, pesticide, explosives, bleaching paper

U- Prior uses: pryotechnics, mouthwash

Potassium chlorate Calcium chlorate Sodium perchlorate, etc

T-­‐  Oxidizer=  MetHb,  hemolysis,  renal  failure  

 

M-­‐  FYI-­‐  Perchlorates=    Also  oxidizers  but  more  stable  

Coal Tar Products Sources: wood creosote= beach wood

(phenol, cresols, guaiacols, xylenols)

coal tar creosote= by-product of coal tar

(85% polycyclic aromatic hydrocarbons (PAH))

U- Wood: wood protectant

Coal tar: wood preservative (railroad ties), Rx for psoriasis

T- Dermal irritant, pulmonary= restrictive/ obstructive

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Diamines

U- Hydrazine= Rocket fuel and reducing agent, insecticides, plastics

T- Hydrazine=INH-like effects (seizures, hepatitis, also MetHb)

T- Irritant/ sensitizer (dermal & pulmonary), lupus-like

Hydrazine TDI

Diamine (Hydrazine) Hexamethylene diamine Toluene-2,4-diamine (TDI) 2-methyl-1,4- benzenediamene

O-Phenylenediamine (OPD)P-Phenylenediamine (PPD)

U- OPD: dyes, fungicides, vet antihelminthic

U- PPD: hair dyes and henna tattoos

T-­‐  OPD=severe  urticaria/dermatitis  (eyeà  blindness)  

PPD

Diamines  (continued…)  

Dimethylacetamide (DMAC)

U- Paint remover, solvent for plastics (dissolves PVC)

Smells like fish/ ammonia

T- Potent hepatotoxin: é LFT, jaundice, hepatomegaly, liver necrosis

T- Irritant: esophagitis, conjunctivitis, dermal burn

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Dimethylformamide (DMF) “Universal Solvent”

U- Penetrates most plastics (makes them swell)

I- Acrylic fiber production, paint strippers

Vehicle for transdermal drug delivery

T- Potent hepatotoxin (Centrolobular necrosis, microvesicular steatosis)

T- Disulfiram rxn and Degreasers’ Flush (also trichloroethylene)

T- Pulm irritant

Dinitrobenzene

U- EXPLOSIVES, spandex, dyes

T- Retrobulbar neuritis & optic neuropathy

T- MetHb (potent)

T- Subacute hepatic necrosis, aplastic anemia

T- May have bitter almond odor, hair/skin/ eye yellowing

Dinitrotoluene (DNT)

U- EXPLOSIVES, diisocyanate production, dyes

T- Uncouples oxidative phosphorylation

T- MetHb

T- Hemolytic anemia

T- Retrobulbar & optic neuropathy

M- Turns skin yellow

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Epichlorhydrin

U- Highly reactiveà plastics production

I- Production of dye, lubricants, adhesives, drugs

T- Strong Irritant (sensitizer): respiratory, dermal, ocular

T- Nephrotoxicity, CNS depression, hypotension

M- Penetrates rubber

M- Sweet, chloroform odor has poor warning property

Ethylene Dibromide (EDB)(AKA Dibromoethane)

U- Replaced dibromochloropropane as nematicide

U- Fumigant (grain- banned 1948), fire extinguishers, lead scavenger in gasoline

T- Hepatotoxicity (GSSH depletion)

T- Strong irritant (dermal, pulmonary)

Ethylenediamine (EDA)

U- Dyes, solvent, emulsifier (skin creams/ latex)

U- Drug production:

(EDTA, imidazolines, aminophylline, antihistamines)

T- Sensitizer (contact dermatitis, occ asthma)

T- MetHb

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Fluoride Compounds

U- NaF: electroplating, toothpaste/ water additive

HF: cleaning brick/ rust, glass etching

T- Chelates divalent cations (Ca++, Mg++), results in ê Mg/ Ca,

é K = ventricular fibrillation

T- Chronic= fluorosis: increased bone density, calcification of ligaments, hyperostosis, white-brown dental spots (axial osteosclerosis/ nerve compression)

Hexachloro-1,3-Butadiene (HCBD)

U- Heat transfer liquid (transformers/ hydraulic fluid)

U- Fumigant in vineyards (don’t confuse with Bordeaux= copper sulfate)

T- Irritant (Pulmonary hemorrhage)

T- Hepatic fatty degeneration

T- Renal tubular necrosis, tubular adenomas

Isocyanates

U- Producing polyurethane polymers

(don’t confuse with anilineà also a polyurethane precursor)

U- Methylisocyanate (MIC)- production of carbamates

MIC

T- MIC: Major irritant (pulm, derm, ocular)

T- TDI: Occupational asthma and HP (Hypersensitivity Pneumonitis)

Methylisocyanate (MIC) Toluene diisocyanate (TDI)

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Maleic Anhydride

U- Enamels, bonding, synthesis of malathion

T- Allergic sensitizer (occupational asthma)

Hypersensitivity pneumonitis (HP) = extrinsic allergic alveolitis = Immunologic

T- Irritant (dermal, ocular)

Mercaptans Chemicals with a –SH group (noxious≈ cabbage)

U- Odorant (natural gas= t-butylmercaptan)

U- Intermediate in synthesis of fuels, pesticides…

Mercaptomethane

T- Irritant (derm, mucous membrane, respiratory)

T- MetHb & hemolysis (worse in G6PD deficiency)

Nitriles Chemicals with a –CN

U- Solvents (eg. artificial nail remover), reagents

Acetonitrile

acetonitrile propane nitrile butanenitrile

T- Liberation of –CN à Cellular asphyxiant

T- Irritants (derm, mucous membrane, ocular)

M- Prolonged observation for delayed CN toxicity

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PhosphorusPhosphides U- Phosphorus- Making phosphates, detergents, fertilizer, match tips

(red) phosphorus

U- Zn & Al phosphide: Insecticides, rodenticides

Zn Phosphide Red

Phosphorus

T- Yellow: strong oxidizer, causes burns (Red is benign)

Ingestion:

1. “smoking”, glowing stool, smells of garlic

2. Asymptomatic (hrs-weeks)

3. Hepatic/ renal failure

Chronic: “Phossy Jaw”- mandibular necrosis

T- Phospine gas: cellular asphyxiant + pulm edema + Hepatic/Renal failure

Phthalates

U- Plasticizing for vinyl, softens PVC

diethylhexyl phthalate

T- Controversial whether phthalates have health

effects. Some claim association with asthma, “sick-

building syndrome”, or endocrine problems but little

supporting data

T- Diethylhexyl Phthalate (DEHP)= occ asthma

Polymers

*Diverse group of plastics*

One class= Fluoropolymer plastics:

Polytetrafluoroethylene (PTFE = Teflon)

tetrafluoroethylene

T- Polymer Fume Fever (heating polymers)

-Pulm irritant, flu-like syndrome (similar to Metal Fume Fever)

-Resolves in 24-48 hrs

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Resins

Resins = Plastics

Combustion can liberate: CO, CN, phosgene

Styrene U- Styrene = Styrofoam

Also ABS (acrylonitrile butadiene styrene), SBR (styrene butadiene rubber) plastics

T- “Styrene Sickness”: HA/fatigue/weakness, intoxicated after exp to vapor

T- Peripheral neuropathy

T- CNS (balance, memory, color vision)

T- Chronic= Hearing loss

Trimellitic Anhydride U- Plasticizer for polymers (PVC)

T- Sensitizer/ irritant; 4 syndromes:

1. Asthma/ rhinitis (IgE)

2. Irritant syndrome (dust/ fumes)

3. Late respiratory systemic syndrome (LRSS)

“Trimellitic Flu”- Like MFF, 4-12 hours after shift.

Symptoms include: cough/wheezing, muscle & joint paint and fever

4. Hypersensitivity pneumonitis + hemolytic anemia

“Pulmonary disease- anemia” (PDA)

Dyspnea, cough, hemoptysis, anemia

May lead to restrictive lung dz; pulm hemosiderosis

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Xylidine

U- Making dyes/ pharmaceuticals, gas additive…

T- Acute: MetHb, cyanosis, intoxication

Xylidine O-xylidine 2-6-methylaniline

Key Words…

Group by some reoccurring themes

Irritants - Acrolein

- Acrylates

- Epichlorohydrin

- Ethylene Dibromide (EDB)

- Ethylenediamine

- Methylisocyanate (MIC)

- Mercaptans

-Many more

-So many, decide if this category works for you...

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Peripheral Neuropathy

-Acrylamide

-Bromide (Methyl)

-Carbon disulfide

-Styrene

-Trichloroethylene

Hepatotoxins -Dimethylacetamide (DMAC): Necrosis, jaundice

-Dimethylformamide (DMF): steatosis

-Hexachloro-1,3-Butadiene (HCBD): fatty degen

-Phosphorus (yellow or white)

-Methylenedianiline: Hepatitis (Epping jaundice)

MetHb Inducers

-Chlorates

-Dinitrobenzene (potent)

-Dinitrotoluene (DNT)

-Ethylenediamine

-Mercaptans

-Xylidine

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SensitizersPulmonary= Occupational Asthma

- Maleic Anhydride: Allergic & hypersensitivity pulm dz

- Trimellitic Anhydride: Asthma, “Trimellitic Flu” (HP)

- Ethylenediamine (EDA): occup asthma, contact dermatitis

- Toluene diisocyante (TDI)/ isocyanates: (#1 occ asthma)

- Diethylhexyl Phthalate (DEHP): occ asthma

Hypersensitivity Pneumonitis (HP)Some overlap with previous slide

-  Anhydrides: -  Maleic Anhydride -  Trimellitic Anhydride

-  Isocyanates (TDI, MDI)

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Good Luck!!

stephen.munday@sharp.com

Which is associated with dermatitis and peripheral neuropathy?

a)  Acrylamide

b)  Acrylate

c)  Acrolein

d)  Azides

Which is associated with dermatitis and peripheral neuropathy?

a) Acrylamide b)  Acrylate

c)  Acrolein

d)  Azides

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Which has cellular asphyxiant properties similar to cyanide?

a)  Anilines

b)  Azides

c)  Mercaptans

d)  Styrene

Which has cellular asphyxiant properties similar to cyanide?

a)  Anilines

b) Azides c)  Mercaptans

d)  Styrene

Which of the following can cause anemia and pulmonary disorder?

a)  Carbon Disulfide

b)  Diamines

c)  Isocyanates

d)  TMA (Trimellitic Anhydride)

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Which of the following can cause anemia and pulmonary disorder?

a)  Carbon Disulfide

b)  Diamines

c)  Isocyanates

d) TMA (Trimellitic Anhydride)

Which of the following is associated with microvesicular steatosis?

a)  Dimethylacetamide (DMAC)

b)  Dimethylformamide (DMF)

c)  Dinitrobenzene

d)  Nitriles

Which of the following is associated with microvesicular steatosis?

a)  Dimethylacetamide (DMAC)

b) Dimethylformamide (DMF) c)  Dinitrobenzene

d)  Nitriles

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Which of the following is associated with methemoglobin production?

a)  Aniline

b)  Butadiene

c)  Epichlorohydrin

d)  Styrene

Which of the following is associated with methemoglobin production?

a) Aniline b)  Butadiene

c)  Epichlorohydrin

d)  Styrene