Other Factors That Affect Toxicity

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OtherFactors That Affect Toxicity
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Routes of Exposure

• There are 3 primary (1 secondary) routes of
  exposure
• DERMAL
• INHALATION
• ORAL

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Routes of ExposureDermal

• The most common way that we come in contact with
  chemicals
• Intact skin is quite resistant to many chemicals.
• As a general rule
• inorganic chemicals are not absorbed by intact
  skin
• organic chemicals may or may not be absorbed
  depending upon various factors

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Dermal Absorption of Organics

• Dry powder organics are not readily absorbed
  however, the same chemical in aqueous form will
  be
• Oily formulations penetrate more readily than
  aqueous

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Dermal Absorption of Organics

• Some substances can aid dermal absorption Ex.
  Dimethyl Sulfoxide (DMSO) is quickly absorbed and
  may be a carrier of other substances

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Open Skin

• Abraded skin is a poor barrier and will likely
  lead to systemic exposures absorption through
  abraded skin is not true dermal absorption is it?

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Routes of ExposureInhalation

• Inhalation is the second most common route of
  exposure
• The surface of the lungs is a poor barrier to
  toxins.

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Which is Bigger?
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Size Does Matter

• The lungs have a much, MUCH greater surface area
  than the skin
• The human skin is about 20 ft2
• The human lung is about 750 ft2

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Inhalation Route

• The lung tissue is a delicate membrane no more
  than 1 to 2 cells thick, separating gases from
  red blood cells.
• The ability to readily allow the transfer of
  gases across this membrane (the primary function
  of the lungs) also allows unwanted vapors and
  gases to pass through..and perhaps small
  particles

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The Lungs are an Open Window to the world
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Inhalation Route

• The delicate tissues of the lung permits
  systemic exposures however, the lung tissues
  are also easily damaged.
• Toxins such as asbestos and silica cause (among
  others) a disease known as fibrosis.
• Fibrosis is the scarring of lung tissue which
  thickens the lung walls and reduces function

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Inhalation Route

• If a chemical cannot become airborne, it cannot
  enter the body through the respiratory route.
• Chemicals become airborne in 2 ways
• Particles (dusts, mists, fumes)
• Individual atoms or molecules (gases or vapors)

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Inhalation Route

• Dust particles can only become airborne if they
  are a certain size
• inhalable,
• thoracic,
• respirable

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Inhalation Route

• Larger particles fall out of the air or otherwise
  fail to enter the respiratory tract
• Smaller particles are inhaled and exhaled much
  like a gas or vapor
• Gases and vapors may readily become systemic
  toxins and be taken to virtually any (target)
  organ

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Route of ExposureIngestion (Oral)

• The 3rd Primary route of exposure is oral
• Primary exposure toxins mixed with food and
  water - the G.I. tract becomes the first organ to
  contact these potential toxins
• Absorption can occur all along the G.I. tract
• It is easier for infants to absorb through the
  stomach than for adults

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Oral Route

• Infants up to age 9 months have alkaline (pH over
  7) in their stomachs. What about adults?
• This is the reason that nitrates are highly toxic
  to infants and not so much to adults (acutely)
  alkaline pH enhances nitrate reduction

BLUE BABY - Nitrates greatly reduce oxygen
transport. Low oxygen in the blood will cause
infants to have blue-colored skin.
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Nitrates

• Nitrate concentration in water supplies can often
  be as high as 3 ppm and will not adversely
  affect taste
• As little as 10 ppm of nitrates can cause adverse
  effects to infants
• Historically, blue babies have resulted from
  preparing formula from water that has excessive
  nitrate levels

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Combinations

• It is somewhat rare that toxins have only one
  route of entry (only common with intentional
  intoxication remember Toffana?)
• Dermal exposure may becomes oral how?

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Combination Exposures

• When an individual contacts a toxin, fails to
  wash their hands prior to eating, drinking,
  smoking, etc.
• Inhalation exposure becomes ingestion?
• When inhaled gases/particles are coughed up and
  subsequently ingested vice-versa

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Influence of Route on Toxicity

• SOME chemicals are toxic by all 3 routes
• For example
• organo-phosphates (OP) like Parathion inhibit
  cholinesterase enzymes regardless of how they
  enter the body dermal, respiration, or oral

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Influence of Route on Toxicity

• Cholinesterase, a neurotransmitter, regulates
  nerve impulses
• Cholinesterase inhibition allows choline esters
  such as acetylcholine to remain activated which
  in turn causes repeated firing of parasympathetic
  nerves.
• Pinpoint pupils and excessive salivation are
  symptoms may cause death

What nerve gases act like parathion?
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Influence of Route on Toxicity

• MOST chemicals ARE NOT equally toxic through all
  3 routes of exposure.
• Vitamin D
• highly toxic acutely through the oral route
• nontoxic acutely and chronically by the dermal
  route
• no studies are known for the inhalation route
  why would we? - not a legitimate concern

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Influence of Route on Toxicity

• Elemental Mercury (Hg), a liquid is not an
  acute hazard by any route.
• Mercury is chronically toxic by ingestion
• Mercury vapors are extremely toxic by inhalation
• A child who breaks a thermometer and plays with
  it is not harmed but if spilled, a serious,
  chronic exposure may result
• What else did you learn about Hg?

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Elemental Mercury

• Who is at risk occupation-wise?
• What about contact with silver/gold?
• Describe what happens to Hg when it is spilled.
• How should it be cleaned up?
• What about mercury amalgams? health hazard?

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Mercury Meter

• Meters like this Jerome Mercury Meter work by
  drawing ambient air across a window of gold foil.
  The mercury quickly (and efficiently plates-out
  on the gold and can be readily quantified

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Influence of Route on Toxicity

• 2 Reasons Why Toxicity Varies With Route of
  Exposure
• Quantity
• Pathway
• The route of exposure that allows the greatest
  quantity into the body is the most toxic
• Which route has the weakest barrier?

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Influence of Route on Toxicity

• The pathway depends upon
• the sequence
• the physiological/metabolic events that occur
  along the way and,
• the target organs effected
• Examples G.I. organisms may degrade toxins in
  the intestines Toxins in the liver may be
  detoxified, rendered more toxic, or not affected
  at all and some chemicals may go directly to the
  lymphatic system and thus enter the blood

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Factors That Influence ToxicitySpecies

• The science of toxicology depends heavily upon
  data gathered from animal studies.
• We use this to make judgments about the toxicity
  to humans.
• Toxicologists must be aware of species
  differences in order to estimate human toxicity.

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Species

• Primates, such as this Macaque Monkey, are
  considered to be the closest reliable models to
  humans
• They are expensive and much controversy surrounds
  using such an advanced primate for toxicity
  studies

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Species Toxicity - Methanol CH3OH

• Methanol is highly toxic to humans and primates
  both acutely and chronically, by inhalation and
  ingestion.
• It is much less toxic (even non-toxic in some
  cases) to other species.
• No species other than humans experience ocular
  damage from methanol

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Species Toxicity - TOCP

• TOCP (tri-ortho-cresylphosphate) an industrial
  chemical is toxic acutely and chronically, by all
  routes of exposure to humans and chickens but not
  to dogs or rats (2 common animal models)
• TOCP demylenates nerve fibers
• May result in permanent paralysis

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TOCP Jamaica Ginger Jake

• In the early 1920s, when alcoholic beverages were
  prohibited a popular way to get a buzz was to
  imbibe patent medicines which typically
  contained 70 ethanol (140 proof!)
• One of the most popular, Ginger Jake
• A Boston Co., trying to save money on the
  concoction, used TOCP to cut the jake
• Thousands of citizens, mostly southerners, were
  stricken with permanent paralysis

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Species

• Many of the differences between species can be
  explained by variations in metabolic/physiological
  pathways.
• These differences in pathways typically mean that
  one species can manage or repair the ill effects
  of one toxin while another may not be successful
  doing so
• What do Humans and Dalmatians have in common?
  Answer They both concentrate uric acid causes
  kidney/bladder stones and gout

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Species

• In some incidences, physiological differences in
  species results in toxicity variation
• For example, rats do not vomit. Therefore, if a
  toxin is given to them via ingestion route, they
  will have no choice other than to absorb,
  whereas, as Ottoboni puts it, dogs vomit on
  command and would not be injured by similar
  toxins

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Red Squill

• A botantical rodenticide made from the
  Mediterranean squill plant.
• Red Squill will cause animals other than rats to
  vomit and thus is only toxic to those that cant
  vomit

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Species

• This discussion of species variation is most
  important when toxicologist are selecting animals
  to test for subsequent extrapolation to human
  toxicity.
• There is no perfect animal model
• We think of primates as being the closest to
  humans however, as we noted, they would not help
  with methanol and nitrobenzene

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Species

• Fortunately, the similarities among mammals are
  more numerous than the differences.
• On the molecular level, humans even share many
  similarities to some single cell organisms for
  example the TCA cycle is the same in almost all
  living organisms

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Age

• We tend to examine the interesting differences
  between the very young and adults.
• For many substances, toxicity is higher for
  children than adults for others, the reverse may
  be true.
• Example DDT is not acutely toxic to baby rats.
  Acute toxicity increases with age.
• The opposite is true of the OP Parathion

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Age

• These differences are primarily due to hepatic
  microsomal enzyme systems (i.e. P450 MFO)
• Underdeveloped MES will either convert a
  substance to a less toxic material (which happens
  most often) or a more toxic materials (which
  happens less often).
• Therefore an underdeveloped MES will mean that
  sometimes a child will be more adversely affected
  by a given xenobiotic and at other times, will be
  less adversely affected

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Age

• Generally, we consider that children are more
  affected by exposures to chemicals than adults
  because
• Children consume more food per body weight
• Children have more quickly dividing cells and
  therefore more opportunities for DNA damage
• Children may be more sensitive than adults to the
  toxic effects of chemicals (children are harmed
  by smaller doses than adults)

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Sex

• We associate most differences in chemical
  sensitivity based upon the differences in
  reproductive processes
• Outside of this, we know very little about the
  differences in toxicity based upon sex there
  are animal studies to suggest that differences
  exist
• Example male rats are 10X more sensitive to DDT
  liver damage than female rats

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Sex

• Example Some OPs indicate higher sensitivity in
  female rats and mice while others have reverse
  sensitivity
• We believe that since anatomical and
  physiological differences in male and female are
  due to hormones, it is assumed that toxicity
  differences are due to these hormones.
• What else might account for differences?

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Nutrition

• Diet plays an important role in chemical toxicity
• Diets complete in protein and vitamins help
  protect the individual from various chemical
  toxicity
• Additionally, studies have shown that limiting
  the total intake while eating nutritionally
  balanced diets also reduces the occurrence of
  certain tumors

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State of Health

• An individuals response to toxicants is
  influenced by both his/her physical and emotional
  state of being.
• Example lung or liver disease greatly reduces
  the individuals ability to detoxify
• Example simple table salt (NaCl) is harmless to
  healthy individuals however, it can be very
  damaging to individuals with kidney damage or
  certain heart conditions

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State of Health

• We typically DONT test animals who are in poor
  physical condition therefore we have limited
  information on animal studies and state of
  health.
• Its accepted practice to study animals in top,
  healthy condition in order to perform valid
  toxicology experiments
• It is fairly intuitive that state of health is a
  major factor in fighting toxicity

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State of Health

• Our state of mental and emotional health also
  effects toxicity however, it is less tangible
  and harder to study.
• Studies have shown that stressed animals are more
  likely to acquire certain cancers and allergens
  are more effective on stressed animals as well.
• Studies on human outcomes, particularly with
  cancer treatment have indicated that stress plays
  a major role in the individuals ability or lack
  of ability to fight cancer.

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Biochemical Individuality

• An individuals unique biochemical makeup will
  also determine reaction to toxicants
• We generally call this phenomenon INDVIDUAL
  SUSCEPTIBILITY
• The most obvious I.S. is through acute exposure
  reactions
• There is no such thing as a single dose having
  the exact same degree of effect on all individuals

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Biochemical Individuality

• For one person, a single aspirin will cure a
  headache, while another will need 2, another 3,
  etc.
• Similarly, alcohol tolerance some individuals
  will get high on a single beer while another may
  need a six-pack (controlling for body size)
• I.S. occurs in all species. That is the reason
  we work with LD50, which is an average, rather
  than an absolute value.

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Biochemical Individuality

• Example 10 mg/kg of Parathion will only kill
  approximately 50 of a group of rats to which it
  is administered
• The remaining 50 will require a larger dose.
• Among the half that died, some would have
  succumbed to a lower dose.
• Therefore, the I.S. of the entire group is quite
  different among individuals within the group.

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Biochemical Individuality

• We can explain some of the I.S. through genetic
  differences.
• There are a number of genetic traits that allow
  one individual to be more or less susceptible
  than another.
• Example Humans who have fragile RBCs are more
  susceptible to hemolytic agents than those who
  dont

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Biochemical Individuality

• Example Individuals with Xeroderma Pigmentosa, a
  disease that results from genetic deficiency in
  DNA-repair of certain skin processes are more
  susceptible to UV light and are more likely than
  the normal population to get skin cancer
• Albinos and fair-skinned individuals are also
  more susceptible to UV damage

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Xeroderma Pigmentosa
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Biochemical Individuality

• Genetic variations in susceptibility to toxicants
  are often referred to as genetic defects This
  is actually a misnomer because some genetic
  defects are actually protective.
• Individuals born with the lowered ability to
  produce AHH (aryl hydrocarbon hydroxylase) do not
  bioactivate BaP
• This may explain why some smokers never get cancer

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Presence of Other Chemicals

• Antagonism 1 1 something less than 2
• Synergism 1 1 something greater than 2
• Antagonism and Synergism are neither bad nor good
  in and of themselves. A good or bad outcome
  depends upon what overall effect the combination
  of chemicals results in. That is, whether or not
  the outcome is a more toxic or less toxic
  substance.

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Adaptation

• The process whereby exposure to subtoxic doses
  of a chemical renders a person tolerant to
  subsequent doses of the chemical in quantities
  that would be harmful to nonadapted individuals.
• Example The Arsenic Eaters of Styria during
  Mid-1800s Austria, residents ate small quantities
  of AsO3 a couple of times per week. Over time,
  they were able to consume up to 400 mg AsO3
  enough to kill 4 adults

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Adaptation

• Example Alcohol most individuals can remember
  the first time they drank an alcoholic beverage
  it took very little to get buzzed. Later, it may
  take several drinks to get the same buzz
• Example Nicotine most individuals experience
  nausea and dizziness following the first
  cigarette they smoked. Later, they have none of
  the original symptoms

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Adaptation

• Adaptive (Inducible) Enzymes are believed to be
  responsible for most adaptive behavior.
• Example Yeast which metabolize glucose, moved to
  a galactose medium will eventually adapt to
  metabolize the new sugar along with retaining
  the ability to metabolize glucose

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Light

• Not a major factor in toxicity however, several
  examples show that light, both natural and
  artificial can have effect upon toxic exposure
  outcomes
• Example infants and bilirubin. Bilirubin is a
  yellow waste product that occurs in infants
  shortly after birth (excess RBCs are destroyed by
  the body shortly after birth). Normally,
  bilirubin is promptly metabolized. When it is
  not, neonatal jaudice occurs. Light is a safe
  and effective treatment it enhances bilirubin
  metabolism.

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Neonatal Jaundice
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Light

• Vitamin D Exposure to sunlight will help
  prevent the disease rickets a bone disease
  that leaves its victims deformed.
• SAD Seasonal Affective Disorder somewhat
  controversial SAD is believed to be responsible
  for individuals becoming depressed during the
  fall and winter months which coincide with
  reduced sunlight hours. There have been tests
  with light boxes that show marked improvement
  for those with SAD

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Light Box to Treat SAD
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Rickets

• Children with rickets have a completely
  preventable, horrible disease. Simple, cheap and
  effective doses of vitamin D along with sunlight
  provide all that is necessary to prevent this
  disease.