Neuro

Question 1

Agents known to delay repolarization

Answer 1

Due to prolongation of opening of Na channels

DDT (organochlorine insecticide)
Pyrethroid insecticides

Question 2

Toluene

Answer 2

paints, lacquers, thinners, cleaning agents, glues, gasoline

Inhalation is the primary route of exposure, though skin contact occurs frequently. Toluene is a favorite of solvent abusers, who intentionally inhale high concentrations of the VOC.

well absorbed from the lungs and GI tract. It rapidly accumulates in the brain, and subsequently, is deposited in other tissues according to their lipid content,

The CNS is the primary target organ

Klaassen, Curtis D.; Watkins, John B.. Casarett & Doull’s Essentials of Toxicology, Third Edition (Lange) . McGraw-Hill Education. Kindle Edition.

Question 3

metronidazole

Answer 3

peripheral neuropathy characterized by paraesthesias, dysesthesias, headaches, glossitis, urticaria, and pruritus in addition to other somatosensory disorders.

an irreversible sensorimotor deficit in the lower extremities of humans

reduced to the highly reactive and toxic hydroxylamine intermediate and binds to cellular macromolecules including proteins and DNA

neurons and glia appear to be equally susceptible

Klaassen, Curtis D.. Casarett & Doull’s Toxicology: The Basic Science of Poisons, 9th Edition (p. 857). McGraw-Hill Education. Kindle Edition.

Question 4

Myelin Toxicants

Answer 4

Hexachlorophene • Used in antimicrobial soaps (e.g.,  Phisohex ™) Myelin damage when used on very young children

Triethyl • tin Used in marine paints to prevent algal growth

Amiodarone, perhexilene • Inclusions (phospholipidosis ) in Schwann cells

Associated with slowed nerve conduction velocity • E.g. topical DMSO treatment

Question 5

n-Hexane; 2, 5-HD, carbon disulfide

Answer 5

crosslinking agents - impair axonal transport

Question 6

MPTP

Answer 6

street drug contaminant that caused Parkinson’s

very lipophilic; taken up by astrocytes and converted to MPP+ (toxic metabolite) by MAO-B enzyme

MPP+ taken up by dopamine receptors -> inhibits mitochondrial complex 1 (no ATP synthesis)

Question 7

Carbon monoxide

Answer 7

cortical neurons, necrosis of globus pallidus

Question 8

Methanol

Answer 8

toxic to retina

primates > rats due to abundant folate in rodents

Question 9

Triorthocresyl Phosphate (TOCP)

Answer 9

Used as fire retardant, in manufacturing for lacquers and varnishes as a plasticizer

During the Prohibition Era in the U.S., TOCP was component of some bootleg liquor

Individuals who ingested the adulterated beverages developed a spastic gait called “ginger jake ” walk

Neuropathy was unrelated to acetylcholinesterase inhibition (note structure)

Occurred days to weeks after exposure — “ o rgano p hosphorousi nduced delayed, hence the description d elayed n europathy” (OPIDN)

Neuropathy involved peripheral nerves “dying back” neuropathy plus degeneration of ascending and descending spinal cord tracks • Hence another acronym “OPinduced delayed polyneuropathy” (OPIDP)

Question 10

Organic solvents

Answer 10

ethyl benzene, trichloroethylene (ototoxic)

Question 11

isoniazid

Answer 11

peripheral nerve damage

most pronounced in people who are slow acetylators (NAT2 polymorphism)

Question 12

tardive dyskinesia

Answer 12

patient is left with a permanent disability that includes prominent facial grimaces

phenothiazines, which have been used to treat chronic schizophrenia for long periods of time,

Klaassen, Curtis D.. Casarett & Doull’s Toxicology: The Basic Science of Poisons, 9th Edition (p. 843). McGraw-Hill Education. Kindle Edition.

Question 13

Cocaine

Answer 13

blocks the reuptake of dopamine (DA), norepinephrine, and serotonin at nerve terminals in the CNS, and causes release of DA from storage vesicles.

Klaassen, Curtis D.. Casarett & Doull’s Toxicology: The Basic Science of Poisons, 9th Edition (p. 859). McGraw-Hill Education. Kindle Edition.

Question 14

Zinc

Answer 14

intranasal -> olfactory neurons

Question 15

botulinum toxin

Answer 15

Zn-protease that hydrolyzes the fusion proteins required for exocytosis of the neurotransmitter acetylcholine preventing its release and leading to paralysis.

Klaassen, Curtis D.. Casarett & Doull’s Toxicology: The Basic Science of Poisons, 9th Edition (p. 75). McGraw-Hill Education. Kindle Edition.

Question 16

Glutamate receptor agonists

Answer 16

domoic acid (shellfish; hippocampus), kainate

excitotoxins - binding to glutamate receptor results in opening of calcium ion channels -> nerve cells swell and die

Glutamate is the main excitatory neurotransmitter of the brain, and its effects are mediated by several subtypes of receptors called excitatory amino acid receptors

Question 17

Toxic Events at the Synapse

Answer 17

Most common cause: failure to properly terminate neurotransmission

Cocaine and amphetamine block reuptake of dopamine and serotonin in the synapse (e.g. inhibition of dopamine transporter [DAT]) • Results in serotonin syndrome, writhing, and abnormal muscle movements (choreiform movements)

Organophosphorous (OP) insecticides inhibit acetylcholinesterase ( activity, thereby preventing degradation of acetylcholine ( • ACh ) AChE Dysregulation of secretion by glands, muscle twitching, diarrhea………… SLUD

Glutamate receptor agonists — ) prolonged stimulation due to poor degradation of nonphysiological ligands (e.g., domoic acid, • kainate ) Causes death to target cell due to influx of calcium ions + water; activation of calcium activated proteases

Question 18

Agents that block opening of sodium channels

Answer 18

tetrodotoxin; saxitoxin

Question 19

Methyl mercury

Answer 19

Prenatal exposure can impair brain development

Question 20

Manganese

Answer 20

neurons of substantia nigra -> Parkinsonism

welders

Question 21

Organophosphorous and carbamate insecticides

Answer 21

inhibit acetylcholinesterase

SLUD; muscle twitching; pinpoint pupils

Treatment - atropine (ACh antagonist) and 2-PAM (reactivates AChE)

OP degraded via Paraoxonases (PONs)

OPs: chlorpyrifos, malathion
carbamates: carbaryl, aldicarb (Temik)

Question 22

Aminoglycoside antibiotics

Answer 22

streptomycin, gentamicin, kanamycin, etc (ototoxic)

Question 23

strychnine

Answer 23

antagonizes the effect of the inhibitory neurotransmitter glycine, and is thus a potent convulsant.

Klaassen, Curtis D.. Casarett & Doull’s Toxicology: The Basic Science of Poisons, 9th Edition (p. 1093). McGraw-Hill Education. Kindle Edition.

Question 24

curare

Answer 24

interference in the conduction of nerve impulses from the motor nerve to skeletal muscle. sensory nerves were left intact.

high affinity for the acetylcholine receptor at the neuromuscular junction. Reversibly inhibits nAChR.

Klaassen, Curtis D.. Casarett & Doull’s Toxicology: The Basic Science of Poisons, 9th Edition (p. 1286). McGraw-Hill Education. Kindle Edition.

Question 25

dimethlaminopropionitrile

Answer 25

affects nerves innervating bladder

Question 26

Rotenone (botanical)

Answer 26

insecticide; piscicide

Question 27

Taxol and colchicine

Answer 27

affect microtubules

taxol - stabilizes microtubules
colchicine - prevents tubulin polymerization

Question 28

batrachotoxin

Answer 28

beetles, frogs; poison darts

irreversibly opens, the sodium channels of nerve cells and prevents them from closing, resulting in paralysis and death. No antidote is known.

Question 29

Carbon disulfide

Answer 29

most significant exposures of humans to CS2 have occurred in the vulcan rubber and viscose rayon industries. High-level exposures of humans to CS2 cause a distal axonopathy that is identical pathologically to that caused by hexane.

ultimate toxicant

also cross-linking of neurofilaments

Klaassen, Curtis D.; Watkins, John B.. Casarett & Doull’s Essentials of Toxicology, Third Edition (Lange) . McGraw-Hill Education. Kindle Edition.

Question 30

acrylamide

Answer 30

peripheral neuropathies in factory workers exposed to high doses.

Klaassen, Curtis D.; Watkins, John B.. Casarett & Doull’s Essentials of Toxicology, Third Edition (Lange) . McGraw-Hill Education. Kindle Edition.

Question 31

HIV-associated dementia (HAD)

Answer 31

is a neurological disorder afflicting many AIDS patients. Exposure to cocaine and amphetamines in AIDS patients results in a synergistic neurotoxicity, which is attenuated by β-estradiol

Klaassen, Curtis D.. Casarett & Doull’s Toxicology: The Basic Science of Poisons, 9th Edition (p. 859). McGraw-Hill Education. Kindle Edition

Question 32

trimethyltin

Answer 32

Organotins are used industrially as plasticizers, antifungal agents, or pesticides. Intoxication with trimethyltin has been associated with a potentially irreversible limbic-cerebellar syndrome

triggers selective apoptosis in specific subregions of the mammalian CNS and specific subsets of immune system cells

hippocampus is particularly vulnerable

Klaassen, Curtis D.. Casarett & Doull’s Toxicology: The Basic Science of Poisons, 9th Edition (p. 847). McGraw-Hill Education. Kindle Edition.

Question 33

methyl n-butyl ketone

Answer 33

axonal degeneration w/ neurofilament swelling

Question 34

hexachlorophene

Answer 34

spongiosis