Chapter 18Toxicology

Introduction

Toxicology is the study of toxins (poisons), how they damage the body, and how the body

can be protected from this damage. Toxins are grouped into classes according to the

particular mechanism they use to damage the body. By figuring out the mechanism a

particular poison uses to damage the body, we can design countermeasures to interfere

with this mechanism, and minimize damage to the body.

DOSAGE

Most people who not scientists believe that even small quantities of poisons cause

permanent damage to body. In fact, our bodies constantly being attacked by every class of poison that exists, and constantly

repairing every kind of damage that poisons can inflict (even cancer).

Why then can some poisons kill us or leave us damaged for life?

Key to this puzzle involves fact that body has limits on how fast it can repair different

kinds of damage. If we ingest large enough quantity of poison in short enough period of

time damage repair cannot keep up with speed of poisoning and we die or damaged

for life. If drink one beer/day for 60 yrs you ingest 102 gallons of alcohol over lifetime.

Drink just one quart of pure alcohol quickly and you die in minutes.

Show Table 18.2.

Different poisons have radically different toxic dosage levels. Most common way of

expressing killer dosage called the "LD50

" of the poison. LD

50 ( Lethal Dosage-50%) is

dosage which will kill half of people (or test animals) who take that quantity of poison all

at once (no repair time).

Since big people usually can repair poison damage faster than small people, body weight

usually factored out of LD50

number. You multiply the LD

50 number by your body

weight (in kg) to figure out how much poison will have a 50/50 chance of killing you. A

person who weighs twice as much can tolerate twice as much poison.

LD50

values vary widely for different kinds of animals. However if LD

50 value extremely

low for one animal it's probably safe to

assume substance is poisonous for all (PROBLEM 6).

CLASSES OF POISONS

I. Corrosives (mechanical)A. AcidsB. BasesC. OxidizersD. Reducing Agents

II. Metabolic Poisons (energy)A. Specific Biochemical InhibitorsB. Heavy Metals

III.Neurotoxins (nervous system)A. AnticholinesterasesB. Acetylcholine AntagonistsC. Cell Membrane Disrupters

IV.Teratogens (birth defects)V. Mutagens (DNA damage)VI.Carcinogens (cancer)

PROBLEM 2.Six classes of toxics?

@ Corrosives, metabolic poisons, neurotoxins, teratogens, mutagens, and

carcinogens.

ROUTE OF ENTRY

How poison gets into body often most important aspect of how poisonous it is.

Examples: Water in stomach good; water in lungs poisonous. KCl in food healthy; in

blood it's "lethal injection." Three most common routes of accidental

entry of poisons into body in order of normal severity of hazard are:

1. Breathing. Substance goes directly (quickly) into bloodstream.

2. Swallowing. Stomach digests poison and small intestine passes slowly into bloodstream.

3. Skin absorbtion. Skin usually a pretty good barrier.

Exceptions exist to order of severity.

PROBLEM 7.Name three routes of entry of toxics into

body. Which fastest?

@ Breathing, swallowing, skin absorbtion. Breathing.

WARNING PROPERTIES

Poisons vary widely in symptoms they give to warn you of toxic dosage. Usually corrosives have best warning properties. Chlorine and ozone can make you feel like lungs on fire yet

do little permanent damage. Neurotoxins often hard to detect until you die. Exception: phosgene (corrosive) smells nice, is delayed-

acting. Hours after breathing it starts to digest lungs. In several days die of

"pulmonary edema" (swollen lungs fill with fluid), drown in own lung fluid.

PROBLEM 1.Define terms.

@:Dose- quantity of toxin ingested.Poison- toxin with low lethal dose.Pulmonary edema- swollen lungs.LD

50 - dose which kills 50% of 1 kg animals

exposed.

Warning property- symptom toxin gives when it is poisoning you.

Corrosives

Corrosive poisons are toxic because they do crude physical damage to tissue. Corrosives

tend to be either acids, bases, or oxidizing agents.

Acids and bases damage tissue by causing hydrolysis of the biopolymers which make it up. Water reacts with polymeric tissue and breaks it down to oligomers and monomers.

Oxidizing agents damage tissue by oxidizing atoms on both the backbone and sidechains of polymeric molecules (tissue) so that the

tissue no longer has the same physical, chemical, or structural properties it is

supposed to have. Tough flexible tissue often becomes brittle or fragile and physically rips

apart.

Table 18.3 pg. 576

PROBLEM 10.Which are corrosives?

@ Sodium hydroxide and ozone.

PROBLEM 11.Type poison causes skin & eye damage?

@ Corrosive.

PROBLEM 8.Warning properties of corrosives?

@ Pain and mechanical damage in tissue contacted.

ACIDS

H2O + COCl

2(phosgene) 2 HCl + CO

2Phosgene used as war gas during WWI. Kills over several days, same ultimate mechanism as crucifixion (drowning in lung fluid). HCl

breaks down lung tissue and body floods lungs with fluid to try to wash it out. Lungs no longer work well (partially digested) so

you drown in fluid. Soldiers dying this way one reason phosgene outlawed war gas.

PROBLEM 9.Which causes pulmonary edema?@ HCl; hydrolyzes lung tissue.

BASES

Bases hydrolyze tissue the same way that acids do except the details of the reaction mechanism are different. Same overall

reaction occurs, however; same reactants, same products.

OXIDIZING AGENTS

Usually replace one or more C or H atoms with one or more O, Cl, F, or Br atoms and

thereby ruin tissue. Another trick: turn S-S into 2 SO

3H groups.

Examples of oxidizing agents: See bottom half of Table 18.3.

Metabolic Poisons

Although strictly speaking "metabolism" involves any biochemical reaction, reactions broken down into those which consume ATP

(anabolism) and those which work toward making ATP

(catabolism). For this reason word "metabolism" usually used to deal with

energy. "Metabolic" poisons are those which in some way interfere with production of

ATP.

Typically metabolic poisons have mild to moderate warning properties.

Two most common subclasses of metabolic poisons are specific biochemical inhibitors

(interfere with some specific enzyme, coenzyme, etc. involved in some way in ATP-making process) and heavy metals (interfere

with a variety of energy-essential biochemicals).

SPECIFIC BIOCHEMICAL INHIBITORS

Three examples of very specific biochemical inhibitors are carbon monoxide, cyanide, and

fluoroacetate.

Carbon monoxide.

Carbon monoxide sticks tenaciously to the "heme" cofactor of hemoglobin (Hb) which

designed to carry oxygen in the bloodstream. "Cofactor" like a coenzyme except that

hemoglobin not an enzyme; it's a transport protein.

If carbon monoxide stuck to heme in hemoglobin protein (complex called

"carboxyhemoglobin") then it can't carry oxygen. No oxygen means no glucose or fat oxidation. This means no ATP - bye bye!

Carbon monoxide sticks 140 X as well to Hb as oxygen does. Need 140 X as much oxygen

to break even.

PROBLEM 12.Three sources of CO.

@ Anything involving combustion, ie. cigarettes, barbeque, automobiles, fireplace,

etc.

PROBLEM 13.Warning properties of CO.

@ Body behaves like it's starved for oxygen; headache (brain hurts), and sleepiness.

Headache takes a while to develop. High dosage puts you to sleep without headache.

PROBLEM 15.What molecule does CO bond to?

@ Hemoglobin.

PROBLEM 19.What's carboxyhemoglobin?

@ CO stuck to Hb.

PROBLEM 20.Treatment for CO poisoning?

@ Breathing pure oxygen is best.

PROBLEM 16.How is CO reversible?

@ Doesn't do any damage per se. As long as lack of oxygen doesn't kill brain cells, once

CO is purged from system carboxyhemoglobin reverts to

oxyhemoglobin and everything returns to normal; no permanent damage.

Cyanide.

Cyanide specifically disables an enzyme designed to enable cytochrome protein to react with oxygen. This one of many steps

necessary for glucose to become oxidized (to produce ATP). Disabled enzyme called

"cytochrome oxidase."

Cyanide poisoning kills by oxygen deprivation like CO, but unlike CO cyanide doesn't prevent oxygen from getting to cells.

Cyanide prevents cells from being able to use oxygen.

Cyanide reversible like CO. Destroyed in body by thiosulfite ion. Best way to help cyanide victim add more thiosulfate to

bloodstream.

PROBLEM 21.Antidote for cyanide poisoning?

@ Thiosulfate.

PROBLEM 17.What does cyanide bind to?

@ Cytochrome oxidase.

PROBLEM 13.Similarity & difference CN- vs. CO?

@ Similarity: both kill by asphixiation.Difference: CO prevents oxygen reaching

cells, CN- prevents usage.

Fluoroacetate.

Fluoroacetate an example of a specific inhibitory metabolic poison which doesn't

affect oxygen activity, but shuts down a vital step in Krebs cycle.

HEAVY METALS

Heavy metal poisons are substances which contain elements from transition metal

regions and bottom left half of "p" region of periodic table. Most common heavy metals involved in poisoning are lead (Pb), arsenic

(As), mercury (Hg), copper (Cu), and chromium (Cr). Other heavy metals not as

available in consumer products.

Cu and Cr used in paint pigments. Pb also used to be in paint pigments but recently phased out. Still used in car batteries and

weights. Hg used to be used in thermometers and As used to be used in rat poison. These

two now phased out of all consumer products.

Heavy metals poison by a variety of different mechanisms, most of which interfere with

enzymes involved in ATP production directly

or indirectly. Common mode of action to tie up sulfhydryl groups of catabolic enzymes.

PROBLEM 22.How do heavy metals harm body?

@ Mostly affect proteins like enzymes. They permanently bind together sulfhydryl groups and mess up proteins' control of their 3and

4 structures.

Reason Pb was phased out of paint pigments is that malnourished inner-city children have

unusual cravings (condition called "pica") and substances like lead paint pigments satisfy these cravings. Huge numbers of

inner-city children had lead poisoning years ago (eating paint chips from dilapidated

buildings) before lead paint pigment banned by law. Lead poisoning does slow brain

damage; children with pica became mentally retarded.

CDC (Centers for Disease Control) set up stations in all major urban areas to monitor

this problem. Children with more than "intervention level" of 10 ug/dL blood lead

treated to lower it.

PROBLEM 30.What's pica, & how related to Pb poisoning?@ Pica is non-food craving associated with bad nutrition. Lead paint pigments among

the substances which can satisfy this craving in children. Poor inner-city children getting

lead poisoning by eating old paint chips containing lead paint pigments.

PROBLEM 32.What federal agency involved with lead

intervention? What is current intervention level for children?

@ CDC. 10 ug/dL lead in blood.

How does heavy metal (ie. Pb) intervention work? How do we remove heavy metal from

body?

"Chelating agents" are substances which extremely effective at removing heavy metals from body. These generally have 2 or more

S, O, or N atoms which bind tightly to metals and keep them from reacting with proteins.

Most commonly used chelating agent called EDTA. Also used in household cleaners to

remove Ca and Mg hard water deposits from sinks, tile, and bathtubs. Very powerful

metal remover. Problem with use in humans is EDTA removes all heavy metal from body, even essential metals necessary for life. Must

supplement essential metals when treating person with EDTA to keep person alive.

Other chelating agent mentioned in text BAL (British Anti-Lewisite) sometimes still used to

treat As poisoning. Developed in WWII to treat soldiers poisoned with As war gas.

PROBLEM 23.What's chelation? Name two chelating

agents.@ Chelation is removal of heavy metal ions

by capturing them with chelating agents. EDTA and BAL are chelating agents.

There other sources of lead ingestion besides paint chips. Drinking water has lead because of use of lead-based solder. Air contains lead from past use of tetraethyllead octane booster

(now outlawed). Soil has natural low lead level, so we ingest lead in food.

Humans can get rid of 2000 ug of lead per day (urine & feces). As long as we ingest less that that amount we can get rid of Pb as fast as we take it in and we live with a constant

low level of Pb in blood (lead equilibrium). If we take in more than 2000 ug of Pb per day it starts to build up in body and blood Pb level rises to dangerous levels. Typical turnover:

about 200 - 300 ug/day.

PROBLEM 24.What's metal equilibrium?

@ Low blood metal level from balanced ingestion & elimination.

PROBLEM 33.Why is Pb in drinking water?

@ Lead solder used on pipes.

PROBLEM 26.Which are metabolic poisons?

@ CO and Hg.

Neurotoxins

Some of most effective poisons on earth. Warning properties inadequate or

nonexistent. Lethal dosages lower than other poisons with exception of a few bacterial

toxins which are specific metabolic poisons (ie. one molecule diphtheria toxin kills entire

cell; shuts down protein synthesis).

Neurotoxins often irreversible. Subacute doses can leave people with permanent nerve

damage.

Two subclasses of neurotoxins: anticholinesterases (nerves can't stop firing) and acetylcholine antagonists, often alkaloids

(nerves shut down). Both interfere with acetylcholine biochemistry.

PROBLEM 36.How does anticholinesterase work?

@ Gunks up enzyme responsible for breaking acetylcholine molecule and stopping

nerve firing. Nerve can't relax.

PROBLEM 38.Name a chemical warfare anticholinesterase

poison.@ Sarin, Tabun, or Soman.

Teratogens

Cause birth defects. Some by crossing placental barrier which separates fetus blood

supply from mother's blood supply and damaging developing fetus, and others by

damaging primitive embryo before placenta develops.

PROBLEM 39.If substance passes thru placenta what is

danger? If harms fetus what is it?

@ Might harm fetus. A teratogen.

Mutagens

Cause mutations in cellular DNA. If mutagen causes damage to DNA of egg or sperm then birth defects can result even if mutagenic chemical not teratogenic per se.

When mutations occur in regular cells body attempts to repair them so that these cells will not produce mutant proteins. Body occasionally makes mistakes repairing mutations and they become permanent.

When enough mutations build up in DNA in same cell cell often becomes cancerous. If cancer cells created faster than body can

destroy them you develop tumors. Tumors eventually mature to point where they spread

widely enough to kill you.

Mutagens determined by means of the "Ames Test." Named after Bruce Ames, inventor. Bacteria genetically engineered to require

histidine in medium to survive (normal bacteria make own histidine). Mutagenic chemicals cause some reverse mutations; bacterial colonies able to grow in medium

lacking histidine are mutants.

PROBLEM 41.Discuss Ames test.

@ Ames test determines if substance is mutagenic; if substance causes mutations in

engineered bacteria some of them will acquire the ability to live in the absence of an

essential amino acid and form colonies on Petri dish.

PROBLEM 40.If a chemical causes mutations in bacteria

what type poison is it?

@ A mutagen.

Carcinogens

Carcinogens and mutagens often the same but there's a subtle difference between these poison classes. Mutagens cause mutations in

bacteria, and may or may not cause mutations in human body cells and/or sex cells. Mutagens do not necessarily cause

cancer. Carcinogens are substances which proved to cause cancer. All carcinogens

probably mutagens but not all mutagens are carcinogens.

Unfortunately carcinogens must still be tested on animals to prove they actually

carcinogens. Ames was trying to replace this kind of testing but discovered too many

otherwise harmless everyday natural chemicals (even some essential biochemicals)

were mutagens. Even if substance causes cancer in lab rats doesn't prove cancer in

humans, but humans match animals better than bacteria.

PROBLEM 42.What's a carcinogen? Difference between

human & animal carcinogens?@ Causes cancer in animals. Unknown.

Carcinogenesis occurs in two stages. In first stage, "initiation," mutagenesis thought to

take place. Cancer does not usually develop until some later injury causes mutant cells to reproduce (to repair injury). Cancerous cells

lose ability to know when to stop reproducing, and they form tumors

("promotion").

PROBLEM 43.PROBLEM 44.

Describe initiation and promotion.@ Initiation: Carcinogen creates "latent"

tumor cells (mutations).Promotion: injury(ies) turn latent cells into

tumors.

Show benzo(a)pyrene carcinogenicity in mice.

Discuss MTD, old Delaney Clause, and new Food Quality Protection Act.

PROBLEM 45.Discuss MTD.

@ MTD, Maximum Tolerated Dose, is highest quantity of toxin animal can tolerate before poisoning occurs. Most mutagens do

not seem to cause cancer below the MTD level. Many innocuous substances cause elevated cancer rate above MTD level.

Poisoning in general elevates cancer rate.

Show natural carcinogens in food slides. Discuss natural and man-made pesticides. Discuss how insect attacks elevate levels of

natural pesticides.

PROBLEM 46.Name 3 carcinogen-containing foods.

@ Choose any three: celery, black pepper, mushrooms, mustard, horseradish, beer &

wine, coffee, tea, lima beans, citrus fruits, bananas, tomatoes.