ACMT Board Review

Miscellaneous Toxins

ACMT Board Review

Miscellaneous Toxicants

Brandon Wills, DO, FACEP, FACMT Fellowship Director, Medical Toxicology Department of Emergency Medicine VCU Medical Center Virginia Poison Center VCU TOX 1

2.2.10 Miscellaneous Toxicants 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 2.2.10.37 Xylidine

Our Gameplan

 Organize your memory

 Using study aids (quick look at ﬂashcards)  60 min: brief review- focus on test rather than content

 20 min: Miscellaneous Toxicants Jeopardy overview

1 Miscellaneous Toxins

Sources

 Dr. Sean Bryant

 Dr. Mike Greenburg

 Sullivan, 2nd Ed  Greenburg, 2nd Ed

 My board review notes

 http://pubchem.ncbi.nlm.nih.gov/ (structures)

Legend for this talk

U= Uses

I= Industry

T= Toxicity

M= Miscellaneous factoids

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

Acrolein = Acrid = IRRITATING

I: Contact herbicide I: WWI Lacrimator

T- Water soluble irritant

T- Cellular toxin via oxygen free radicals

M- Metabolite of cyclophosphamide

2 Miscellaneous Toxins

Propenamide, acrylic amide, Acrylamides akrylamid Heating Starches U- Polymer production (SDS-PAGE), ﬂocculator

T- Axonopathy T- Dermatitis (peeling, red/blue, hyperhidrosis)

T- IARC 2A (poss gyn CA) M- Polymer = non-toxic, Monomer= toxic

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

U- Cross-linking properties (plexiglass)

T- Irritant (skin, MM, and pulmonary) T- Contact dermatitis

M- Penetrates latex/ rubber easily

Dimethylamine Trichlorotriethylamine Benzidine Benzidine Amines β-naphthylamine

Dimethylamine

AZO Dyes

-Vulcanization

3 Miscellaneous Toxins

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

U- Precursor for polyurethane, indigo= blue jean die I- Smells like rotten ﬁsh

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) 10

Azides

U- Airbag accelerant; pesticde, explosives I- Labs and manufacturing plants

T- Cellular asphyxiant, 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)

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

M- Low anion gap (false high Cl)

4 Miscellaneous Toxins

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

U- Monomer for plastics (ABS plastic*), tobacco smoke

T- Irritant (skin and mucous membranes)

T- IARC 2A (lymphohematopoetic, testicular, thyroid, mammary)

*ABS: Acrylonitrile-butadiene-styrene

Carbon Disulﬁde U- Volatile organic solvent I- Rayon, fumigation

T- Acute: Irritant (defatting), disulﬁram rxn T- Chronic: 1. Distal axonopathy 2. Optic nerve (resembles optic neuritis) 3. CV (HTN, CAD) 4. Repro (SAB, prematurity, decreased libido)

Potassium chlorate Calcium chlorate Chlorates Sodium perchlorate, etc

U- Oxidizer, pesticide, explosives, bleaching paper

U- Prior uses: pryotechnics, mouthwash

T- Oxidizer= MetHb, hemolysis, renal failure

M- FYI- Perchlorates= Also oxidizers but more stable

5 Miscellaneous Toxins

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 psoriasis

T- Dermal irritant, pulmonary= restrictive/ obstructive

Cancer d/t PAH (lung, oral, stomach, bladder, scrotal, skin)

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

U- Hydrazine= Rocket fuel (reducer), insecticides, plastics

U- P-phenylenediamine= henna & all hair dyes...

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

T- Hydrazine=INH (seizures, hepatitis, MetHb, skin sensitizer)

Dibromochloropropane (DBCP)

U- Nematicide (D/C’d in 1979)-> replaced by dibromoethane

T- Dermal / ocular irritant

T- Testicular (aspermia, oligospermia)

De Balls Can’t Produce (DBCP)

6 Miscellaneous Toxins

Dimethylacetamide (DMAC)

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

Smells like ﬁsh/ ammonia

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

T- Irritant: esophagitis, conjunctivitis, dermal burn

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 (CLN, steatosis) T- Disulﬁram rxn 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

7 Miscellaneous Toxins

Dinitrotoluene (DNT)

U- EXPLOSIVES, diisocyanate production, dyes

T- Uncouples oxidative phosphorylation

T- MetHb

T- Hemolytic anemia

T- Retrobulbar & optic neuropathy

M- Turns skin yellow

Epichlorhydrin

U- Highly reactive 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)

8 Miscellaneous Toxins

Ethylenediamine (EDA)

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

U- Drug production:

(EDTA, imidazolines, aminophylline, antihistamines)

T- Sensitizer (contact dermatitis, occ asthma)

T- MetHb

Fluoride Compounds

U- NaF: electroplating, toothpaste/ water additive HF: cleaning brick/ rust, glass etching

T- Chelates divalent cations (Ca++, Mg++), results in ↓ Mg/ Ca, ↑ K = ventricular ﬁbrillation

T- Chronic= ﬂuorosis: bone density, calciﬁcation of ligaments, hyperostosis, white-brown dental spots (axial osteosclerosis/ nerve compression) 26

Fuels

U- Energy-producing hydrocarbons

T- PULMONARY (pneumonitis)

M- Jet fuels (kerosene, benzene, xylene, toluene)

JP-7 & JP-8 ∼ pure kerosene

9 Miscellaneous Toxins

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

Methylisocyanate (MIC) Toluene diisocyanate (TDI) Isocyanates MIC

U- Producing polyurethane polymers

(don’t confuse with aniline also a polyurethane precursor) U- Methylisocyanate (MIC)- production of carbamates

T- MIC: Major irritant (pulm, derm, ocular) T- TDI: #1 Occupational asthma (HP)

Maleic Anhydride

U- Enamels, bonding, synthesis of malathion

T- Allergic sensitizer (occupational asthma)

Hypersensitivity pneumonitis (HP)= extrinsic allergic alveolitis= Immunologic

T- Irritant (dermal, ocular)

10 Miscellaneous Toxins

Mercaptans Mercaptomethane

Chemicals with a –SH group (noxious≈ cabbage)

U- Odorant (natural gas= t-butylmercaptan) U- Intermediate in synthesis of fuels, pesticides…

T- Irritant (derm, MM, respiratory)

T- MetHb & hemolysis (worse in G6PD)

acetonitrile propane nitrile Nitriles butanenitrile Acetonitrile Chemicals with a –CN

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

T- Liberation of –CN  Cellular asphyxiant T- Irritants (derm, MM, ocular) M- Prolonged observation for delayed CN toxicity

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

*This compound is also listed under “Diamines”* PPD

U- OPD: dyes, fungicides, vet antihelminthic U- PPD: hair dyes and henna tattoos

T- OPD=severe urticaria/dermatitis (eye blindness)

T- PPD= bladder cancer

11 Miscellaneous Toxins

Phosphorus Red Phosphides Zn Phosphide Phosphorus

U- Making phosphates, detergents, fertilizer, match tips (red)

U- Zn & Al phosphide: Insecticides, rodenticides

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 + #3 above 34

Phthalates diethylhexyl phthalate

U- Plasticizing for vinyl, softens PVC

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 tetrafluoroethylene

*Diverse group of plastics*

One class= Fluoropolymer plastics:

Polytetraﬂuoroethylene (PTFE = Teﬂon)

T- Polymer Fume Fever (heating polymers)

-Pulm irritant, ﬂu-like syndrome (similar to MFF)

-Resolves in 24-48 hrs

12 Miscellaneous Toxins

Resins methylenedianiline

Resins = Plastics

Combustion can liberate: CO, CN, phosgene

Methylenedianiline – Toxic hepatitis (Epping Jaundice)

Anhydrides – Occupational pneumonitis

Styrene

U- Styrene = Styrofoam

Also ABS, SBR 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

4. Hypersensitivity pneumonitis + hemolytic anemia

“Pulmonary disease- anemia” (PDA)

Dyspnea, cough, hemoptysis, anemia May lead to restrictive lung dz; pulm hemosiderosis 39

13 Miscellaneous Toxins

Triorthocresylphosphate (TOCP) U- Plasticizer in lacquer, hydraulic ﬂuid

T- Weak AchE inhibitor (like organophosphate)

Inhibits neuro-target-esterase (NTE)

T- Delayed sensory-motor neuropathy

“O-P ester induced delayed neurotoxicity (OPIDN)”

M- Jamaican Ginger (Jake) adulterated by TOCP

“Jake Walk”= Jake leg paralysis M- Morocco: OPIDN after TOCP adulterated cooking oil 40

Xylidine O-xylidine Xylidine 2-6-methylaniline

U- Making dyes/ pharmaceuticals, gas additive…

T- Acute: MetHb, cyanosis, intoxication

T- Chronic: Liver/ renal damage (animals)

Now…

Group by some reoccurring themes

14 Miscellaneous Toxins

Irritants

- Acrolein

- Acrylates

- Epichlorohydrin

- Ethylene Dibromide (EDB)

- Ethylenediamine

- Methylisocyanate (MIC)

- Mercaptans

-Many more

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

Cancer Causing

-Acrylamides (2A)

-Aromatic Amines (Benzidine, β-naphthylamine) (1): bladder

-Aniline (1): bladder

-P-Phenylenediamine (PPD): bladder, leukemia

-Butadienes (2A): lymphohematopoetic

-Coal tar: lung, oral, stomach, bladder, scrotal, skin

-Vinyl Chloride: Angiosarcoma of liver

-CCl4: Liver

Peripheral Neuropathy

-Acrylamide (A)

-Bromide (Methyl) (A) -Carbon disulﬁde (A)

-Styrene (?)

-TOCP

-Trichloroethylene (M)

15 Miscellaneous Toxins

Hepatotoxins

-Dimethylacetamide (DMAC): Necrosis, jaundice

-Dimethylformamide (DMF): CLN, steatosis

-Hexachloro-1,3-Butadiene (HCBD): fatty degen -Phosphorus (yellow or white)

-Xylidine (in animals; also renal damage)

-Methylenedianiline: Hepatitis (epping jaundice)

MetHb Inducers

-Chlorates

-Dinitrobenzene (potent)

-Dinitrotoluene (DNT)

-Ethylenediamine

-Mercaptans

-Xylidine

Sensitizers Pulmonary= Occupational Asthma

- Anhydrides: occupational pneumonitis (HP)

- 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

16 Miscellaneous Toxins

Hypersensitivity Pneumonitis (HP) Some overlap with previous slide

- Anhydrides/ Maleic Anhydride

- Pyrethrum

- Trimellitic Anhydride - Isocyanates (TDI, MDI)

VCU TOX 51