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Chemistry 1002 Chapter 18Toxicology |
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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. LD50
( 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 LD50 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 LD50 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. Acids
B. Bases
C. Oxidizers
D. Reducing Agents
II. Metabolic Poisons (energy)
A. Specific Biochemical Inhibitors
B. Heavy Metals
III.Neurotoxins (nervous system)
A. Anticholinesterases
B. Acetylcholine Antagonists
C. 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.
LD50 - 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 + COCl2(phosgene)
Æ 2 HCl + CO2
Phosgene 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 SO3H 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 3_ and 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
& faces). 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' 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.
Comments?
Last Revised : Sunday, October 5, 1997
Copyright © 1997
Louisiana State University, Department of Chemistry.
All rights reserved.
http://www.chem.lsu.edu/lucid/courseinfo/chem1002/ch18.html
