RXRS 304

Toxicology

Study of adverse effects of chemical, physical, or biological agents on living organisms

Xenobiotic

Any substance that is foreign to a biological system

Acute toxicity

single or short term exposure to a toxicant

Chronic toxicity

continuous or intermittent exposure to low concentrations of toxicant over time

Adverse drug event

any unwanted or dangerous reaction to a drug

Risk =

Hazard X Exposure

Who was the father of modern toxicology?

Paraclesus: All substances are poisons; it is the dose that differentiates a poison from a remedy

Bioavailability

% of chemical that enters systemic circulation while remaining unchanged

What can affect bioavailability of an orally administered drug?

Drug formulation, GI interactions, biotransformations

Toxicokinetics

what the body does to the toxicantT

Toxicodynamics

What the toxicant does to the body

What are the main organs responsible for eliminating a substance?

Liver and kidney

First pass metabolism

First round of metabolism through the liver

TDI

Tolerable daily intake; how much of a contaminant that can be in food or water to be ingested daily over a lifetime without a significant health risk

Therapeutic index

Determines the relative safety of a drug by comparing curves demonstrating its therapeutic and toxic effects

NOAEL

No observed adverse effect level; largest does w/o AE

LOAEL

Lowest observable adverse effect level; lowest does causing AE

What can cause individual susceptibility to a toxicant

genetics, gender, age

Forensic toxicology

the use of toxicology for the purposes of law

Analytical toxicology

using analytical chemistry to ID chemicals that will cause AE on living organisms

Clinical toxicology

diagnoses and treatment of health problems induced by chemical substances

How was poisoning confirmed in the 1600’s - early 1800’s?

Feeding what the human consumed to animals and observing what happens

Mathieu Orfila

Researched arsenic and how to detect it in tissues of animals

What can be analyzed in order to find out what toxicant was used for poisonings?

body fluids, organ tissues, and other tissues that the substance’s distribution and metabolism would indicate

CO MOA?

CO prevents O₂ from binding to Hgb → suffocation

What is indicative of CO poisoning?

skin of victims is cherry pink in color

What are some unusual specimens that can be collected from victims?

bone marrow (burn victims), hair, maggots

Why is hair a good way to test for toxicants?

it gives a timeline of exposure including concentrations

Half life

time it takes for concentrations to decrease by half

Goal of clinical toxicology

treat poisoning by removing unabsorbed substance, limit any more absorption, and hasten elimination

Pen Ts’ao

created the Chinese Materia Medica that describes 365 poisonous, medicinal plants, and antidotes (2735 B.C.)

Dioscorides

wrote the first text on pharmacology and toxicology (~40-90 A.D.)

Strychnine

Toxic alkaloid that blocks nerves and causes spasms and convulsions; death by asphyxiation after 1-3 painful, conscious hours

Most deadly of the chemicals used in WWI

phosgene

Why was prohibition very unsuccessful

poisonings from tainted alcohol thought to prevent consumption and consumption of MeOH based alcoholic drinks such as wood alcohol

Alexey Navalny

opposer of Putin who was poisoned with Novichok-type nerve agent (AChEi); survived after given antidote (AChE) but died in Siberian prison

What does ricin come from?

castor beans

A chain of ricin

carries out toxic function by breaking down ribosomes and inhibiting protein synthesis

B chain of ricin

allows ricin into cells by binding to to carbohydrates on cell surface

What organs are affected by ricin poisoning?

multiple are affected, death coming the quickest when injected

Is there an antidote for ricin?

No; life support is the only option once poisoned; fluids and vasopressors for hypotension and gastric lavage

Is vaccination a good option to protect from ricin poisoning?

It may be beneficial for those who have occupational exposure, but the general population may not need it.

Michael and Deborah Farrar

She found out he cheated; he felt ill after a trip; they divorced; their house burned down, killing 2/3 kids; he found packages of ricin beans; anti-ricin antibodies found in his system, confirming him being poisoned by her

Georgi Markov

He was shot with a pellet containing ricin via an umbrella gun; went home from work feeling ill and eventually went to the hospital; MDs thought it was septicemia due to hypotension and inc. WBC count; autopsy indicated damage to several vital organs

Vladimir Kostov

Occurred days prior to Markov attempt; this time with a briefcase gun; similar route with pellet containing ricin; he developed a fever that resolved; most of the poison remained in the pellet, saving his life

Cyanide

CN^-; main ingredient in Prussian blue in many famous paintings and in the development of color photos

HCN

Much more toxic form of CN^- synthesized by heating Prussian blue with sulfuric acid

Inorganic cyanides

toxic due to their easy dissolution in water; easy release of CN group to cause toxicity

Organic cyanides (nitriles)

less toxic due to covalent bond making it less likely to release CN group

What can CN^- taste like if ingested?

almond or bitter taste

Why is CN that is used in consumer products not really a danger?

they are typically very stable and will likely not release the toxic CN in its intended use

What is KCN and NaCN used for (toxic)?

as poison baits; insecticides, to poison opossums, and for coyotes/foxes/feral dogs

Bitter cassava

root plant that is commonly eaten by humans containing CN

How is bitter cassava processed to reduce the amount of CN?

grind into flour → soak for 3-5 days → evaporate HCN

CN MOA

1. binds to cytochrome c oxidase → stops energy prod. in mitochondria

2. binds to iron in heme of Hgb → O₂ cannot be transported to tissues

U.S. standard antidote for CN poisoning

1. small inhaled dose of amyl nitrite

2. IV sodium nitrite

3. IV sodium thiosulfate

Ancient uses of CN

• Nero used it to poison members of his family

• Napoleon III used CNs to enhance effectiveness of soldier’s bayonets

John Tawell

1845; poisoned his mistress with CN (prussic acid) by putting it in her beer; she died in agony and foamed at the mouth; he escaped, later caught; attorney claimed that she died from CN in apple seeds, jury was not convinced and he was executed

Grigori Rasputin

Russian peasant who became well acquainted with the Tsar; became influential in politics and during WWI; attempted to be poisoned by being given wines and desserts laced with CN at an aristocrat’s palace; he recalls only getting drunk, and he survived

Zyklon B

HCN (prussic acid) used in gas chambers at Auschwitz to kill ~1M people during the Holocaust

Tylenol poisoning (1982)

capsules in Chicago were found to contain KCN in doses large enough to kill thousands; killed 7 due to tampering; led to development of tamper-proof packaging

Jonestown Massacre

mass suicide by CN-laced punch by an American religious cult

Toffana

created aqua della Toffanina, an arsenic-containing liquid sold as poison; no odor or taste so it could be mixed into foods or drinks; symptoms mistaken for that of cholera

Arsenic toxic MOA

structurally and chemically similar to phosphates → disruption of ATP synthesis in oxidative phosphorylation

How can arsenic be detected in the body?

its metabolism is very slow, so it can be detected even decades after death in the victim’s hair and fingernails

James Marsh

developed the Marsh Test to determine the presence of arsenic

Industrial use of arsenic

poison for pests, medicines, cosmetics, dyes

Why did Napoleon’s hair contain high levels of arsenic?

his bedroom used a bright green, arsenic-based wallpaper

Historical, medicinal uses for arsenic?

• whiten skin in Victorian era

• syphilis treatment before antibiotics

How much arsenic can be in our drinking water, per FDA?

10ppb

The Poison Squad

group of 12 men who were given meals containing different chemicals used as preservatives to test their safety

1906 Pure Food and Drugs Act

ensured the proper labeling of things and also ensured anti-adulteration tactics

CO

carbon monoxide, a gas that is abundant due to human activity and nature

How is CO a silent killer?

It is colorless, odorless, and tasteless → undetectable

CO MOA

CO binds to Hgb; converts oxyhemoglobin to carboxyhemoglobin and disallows Hgb to carry O₂ → hypoxia in tissues → death

Why is CO especially dangerous in terms of Hgb binding affinity?

it binds to Hgb 250 times more strongly than O₂ and once one binds to Hgb, it affect the ability for the other 3 sites to bind to oxygen

Claude Bernard

1857 discovered CO’s binding affinity to Hgb and its ability to cause hypoxia

Is CO poisoning reversible?

Yes, once the person is out of the atmosphere with CO, the process reverses

Hyperbaric Oxygen (HBO)

treatment for CO poisoning by exposing victim to pure oxygen gas in a chamber under pressure

Therapeutic uses of CO

organ transplants and reduces blockages of pulmonary arteries after angioplasty

Nazi use of CO during WWII

they killed ~700k people using CO vans

Jack Kevorkian, MD (1990s)

advocate for medical suicide, used CO as euthanasia agent

Mass CO poisoning in Balvano, Italy

more than 500 died when a coal train derailed in a tunnel, causing little ventilation; they succumbed to CO poisoning

Murder of the Garcia Children

2002, a father put the 6 children to bed with windows shut and blankets covering the outside doors; placed a charcoal BBQ in the hallway outside the bedrooms; 5/6 children died; father given life imprisonment

Attempt to murder Margaret Jones

husband attempted to murder her by drilling a hole through bedroom wall and inserted a pipe leading to the garage and into the exhaust of the car; she woke up to the sound of the running engine; she ran and contacted police; guilty of attempted murder

Ecotoxicology

fate and effects of toxic substances on an ecosystem

Environmental toxicology

how chemicals in the environment affect its subjects

Banned Persistent Organic Pollutants (POPs)

organic pollutants that take 4 half-lives to be removed from the environment (DDT, PCBs)

Bioaccumulation

uptake and accumulation of contaminants from the environment and food; lipophilic

Biomagnification

ingested chemicals concentrate in the GI → inc. concentration in organisms w/ inc. trophic levels (MeHg accumulates in fish)

Organic forms of Hg

the most toxic form such as MeHg

Hg MOA

• binds to active site or critical domain of enzymes to inactivate it or reduce activity

• inactivates Na/K-ATPase in CNS

Occupational poisoning of Hg in the 16th to 20th centuries

mirror-makers that constantly handled Hg-silver or Hg-tin

What did “mad as a hatter” come from?

likely from Hg poisoning of hat makers (symptoms include slurred speech, tremors, irritability)

Major historical, medicinal application of Hg

used for syphilis treatment since the 1400s in various formulations

Karen Wetterhahn

poisoned in her lab by Me₂Hg (DMD) that penetrated her glove while investigating another substance; led to revision of safety standards for gloves and other equipment

Minamata Disaster

1950s; MeHg outbreak from industrial discharge into local waters led to contamination in animals and fish; >600 died; 22 pregnant women ate contaminated fish showed mild to no symptoms but gave birth to infants with severe developmental disabilities

Brominated flame retardants (BDEs)

• found in fabrics, electronics, household dust

• lipophilic, bioaccumulates, and biomagnifies in wildlife and humans

• induces skeletal changes in pups

What are BDEs disruptors of?

endocrine disrupters

perfluoroalkyl chemicals (PFAS)

• hormone disruption (dec. T in men, dec. fertility in women)

• developmental delays/effects in children

• inc. risk cancers, cholesterol levels

• dec. immune system response