Chem. 250

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Chem. 250 12/9 Lecture
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Announcements - I

• 12/2 assigned homework problem solutions also
  posted (soon)
• Turn in Term Project Papers
• Last Homework Assignment
• Chapter 16 1, 4, 5, 6, 7, 8, 14, 15, 16
• (No need to turn in Solutions to be posted by
  Friday)

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Announcements - II

• D. Final Exam
• Wed., 12/16, 515 to 715 pm
• Exam will be 100 points and is NOT cumulative.
• There will be both concept type questions
  (multiple choice or fill in the blank) and
  problems/short essay.

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Toxicity (Ch. 16)- Overview

1. Exposure
2. Dose/Response
3. Fate of Toxic Substances in the Body
4. Types of Effects

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Toxicity- Exposure

• The degree to which a toxic substance will cause
  health problems will depend on the following
  conditions
• Concentration of substance
• Form of substance
• Route of entry to body
• Time period in which body is exposed
• Bodys reaction to toxic substance (only above
  are considered exposure)

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Toxicity- Exposure

• Form of substance
• - The form of the substance will affect how toxic
  compounds pass through barriers (skin, GI tract,
  airways)
• Some examples
• - mercury (methyl mercury vs. inorganic mercury)
• - aerosol particles (coarse vs. fine acidic vs.
  neutral)
• - compounds in specific solvents (e.g.
  dimethylsulfoxide vs. water)
• Any form that makes barrier passage easier
  increases toxicity

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Toxicity- Exposure

• Routes of exposure
• 1. Percutaneous (through skin)
• basis
• - diffusion (pure compounds) very fast for
  gases very slow for solids faster for smaller
  molecules
• - polarity (faster for non-polar compounds)
• - solvent effects (solutes in certain solvents
  like DMSO and acetonitrile have increased
  hazards)
• - people with dermatitis or abrasions are
  affected at lower concentrations
• Examples Worker retrieving tool dropped in vat,
  contact with pesticides when harvesting crops

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Toxicity- Exposure

• Inhalation
• - gases diffuse to surfaces (reversible
  absorption)
• - water soluble gases tend to be absorbed more
  efficiently but often before the lungs
• - lungs tend to be most sensitive organ of
  airways (large surface area and designed for
  diffusion to blood).
• - Effects can be felt quickly

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Toxicity- Exposure

• Inhalation (continued)
• - aerosol particles tend to deposit on surfaces
  irreversibly
• - coarse particles cant follow bends fine
  particles go to lungs ultra-fine particles
  diffuse to surfaces

Air passage
Mean gas trajectory
Gas or ultra-fine particle
Particle trajectory
Random motion brings ultra-fine particle to wall
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Toxicity- Exposure (Inhalation)

• Airways have defense mechanisms (mucous and cilia
  to remove particles)
• Toxic response can be due to passage to blood and
  rest of body (pulmonary problems) or to lung cell
  damage (e.g. asbestos)
• People with asthma can suffer at much lower doses
  than others
• Respiration affects exposure. Heavy work or
  exercise in poor air quality can be harmful.

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Toxicity- Exposure

• 3. Oral
• - Absorption occurs in the gastrointestinal
  tract (GI tract)
• - Less polar compounds are preferentially
  absorbed
• - For acids and bases, absorption of non-ionized
  species is much faster
• - Absorption also depends on pH of organ (2 for
  stomach vs. 6 for intestines)
• - Exposure can occur from contaminated foods
  (e.g. with pesticide or natural toxin present) or
  from incidental ingestion (e.g. lead in toys or
  paint flakes, chemistry lab student eating
  cheetos, my son spraying my toothbrush with
  insect repellent)

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Toxicity- Exposure

• Minimization of Exposure
• Use of protective equipment
• Gloves, protective clothes, goggles (dermal)
• Masks or respirators (inhalation)
• Use of equipment to keep chemicals out of contact
• Use of fume hoods
• Segregation of work space into different regions

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Toxicity- Some questions I

1. Besides concentrations, list three other factors
   that affect how toxic a substance is
2. In which form is capsaicin (a moderate sized
   compound of weak polarity) absorbed better into
   the skin? a) As solid powder b) in water c) in
   acetonitrile
3. Which form of lead in the environment is most
   likely to cause acute exposure problems a) solid
   lead, b) tetraethyl lead, c) lead sulfate
   (moderately soluble in water), d) lead phosphate
   (very insoluble in water)
4. A researcher found that SO2 inhalation causes
   more damage after patients drank lemonade or
   other acidic drinks. Explain why?

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Toxicity- Some questions II

1. A lawyer argues that arsenic in aerosols emitted
   from an incinerator has the same concentration as
   aerosols produced from soil dust in natural dust
   storms. Does this make the incinerator safe? Why
   or why not? What else should a safety expert
   know?
2. Which part of the GI tract would the following
   compound be absorbed in a) nitrous acid (pKa
   3.1), b) aniline (pKa of base cation 4.6) c)
   ethyl amine (pKa of base cation 10.6)?
3. Chelating ligands like EDTA are administrated to
   remove toxic metals. Based on pH considerations
   and on movement across the GI tract in reverse,
   will ligands be more effective in the stomach or
   intestines?

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Toxicity- Dose - Response Relationship

• The concentration of a toxic substance in a body
  (e.g. mg of toxin per kg body weight) is related
  to the response of the body
• Numerous responses are possible (e.g. from
  inhibition of specific enzyme to organ failure to
  death)
• Common responses examined are effective dose
  (ED), toxic dose (TD) and lethal dose (LD)
• Relationship between dose and response is
  generally better behaved for acute toxicity

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Toxicity- Dose - Response Relationship

• Plots are made showing onset of response vs.
  concentration.
• From plots LD50 or ED50 can be determined.
• Log conc. vs. death on probit scale typical
• (1 probit unit 1s)
• From Casarett and Duols Toxicology (2nd Ed.)

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Toxicity- Dose - Response Relationship

• Different compounds can have different response
  curves.
• Compounds with shallow slopes mean large
  variability in effects (often MORE hazordous)
• Compounds with low LD50s are more toxic
• Drugs that have LD range overlapping with ED
  range need close monitoring

From Casarett and Duols Toxicology (2nd Ed.)
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Toxicity- Redistribution in Body

• Movement to target organs/tissue (e.g. Hg to
  nerve tissue)
• Storage Tissue/Organs
• fats (for compounds with large Kows)
• bones (for certain inorganic compounds)
• Organs with High Concentrations
• Liver Kidneys
• Normal because these organs used for chemical
  transformation (liver) or excretion (kidney)

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Toxicity- Fate of Substances

• Toxic compounds in the body can be 1) excreted
  or 2) transformed
• More water soluble compounds tend to be excreted
  more quickly, while lipid soluble compounds can
  have long lifetimes (months)
• A common transformation is enzymatic oxidation in
  the liver (particularly for lipid soluble
  compounds)
• Oxidation can lead to decreases or increases in
  toxicity, but usually leads to faster excretion
  due to increase in polarity

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Toxicity- Fate of Substances

• Some Common Transformations
• Hydroxylation
• Dealkylation (alkyl groups attached to N, O, or
  S)
• Oxidation
• Epoxidation
• Glucuronic Acid Addition

OH
RNHCH3
RNH2 CH2O
RCH3
RCH2OH
RCH2O
O
RCHCH2
RC(OH)HCH2OH
RCH--CH2
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Toxicity- Fate of Substances

• Hypothetical Example
• Moderately polar compound (compound A) is slowly
  eliminated and transformed to product (compound
  B)
• Compound B is eliminated faster than compound A
  (Only reaches low concentration)

Conc.
A elimination only
A transformation only
A both losses
Compound B
Time
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Toxicity- Removal of Substances

• Polar/Water soluble compounds are often
  eliminated through urination
• Volatile compounds can be eliminated by
  exhalation
• Less polar compounds can be removed from liver
  through bile (goes back to GI tract)
• Other routes
• GI tract
• Sweat

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Toxicity- Biotracer Studies

• Exposure is often difficult to assess accurately
• An alternative approach is to directly measure
  concentrations of toxin or metabolites in urine
• Factors affecting exposure then can be studied by
  comparing environmental concentrations with
  detected amounts

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Toxicity- Types of Effects

• Acute Effects
• exposure period is typically short but intense
• effects occur soon after exposure
• effects may be reversible or irreversible
• Chronic Effects
• exposure period is typically over a period of
  time
• effects generally take time to develop (e.g.
  cancer)
• may occur from build up of product (e.g. calcium
  oxalate from ingestion of ethylene glycol)
• may result from bodys reaction to toxin (e.g.
  build up of scar tissue)
• may occur for low probability effects (mutation
  of DNA)
• determining relationship is more difficult

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Toxicity- Chronic Effects

• Teratogens
• Compounds that affect normal development of
  fetuses
• Mutagens
• Cause changes to DNA sequences
• Carcinogens
• Compounds that can lead to the development of
  cancer

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Toxicity- Chronic Effects

• Effects of Carcinogens
• Most carcinogens (or their metabolites) can react
  with and alter DNA
• Carcinogens may react with base pairs (e.g.
  aromatic compounds) or with sugar or phosphate
  parts
• Many changes to DNA sequence have little effect
  (may kill cell or have minor effects)
• Changes to DNA can affect normal mechanisms to
  restrict cell growth
• Proliferation of deformed cells is what leads to
  problems with cancer

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Toxicity- Chronic Effects

• Determination of Carcinogens
• Epidemiological Studies (comparison of
  environmental exposure with effects on
  population)
• Animal Tests (e.g. feeding compounds to rats or
  mice)
• Ames Test (bacterial screening test for mutagens)

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Toxicity- More questions I

1. The LD50 for paraquat is about 100 mg/kg.
   Estimate the amount of paraquat that would need
   to be ingested by a typical 50 kg woman to just
   die from it.
2. Why might it be prudent to limit exposures of
   toxic compounds to several orders of magnitude
   under the LD50?
3. What are possible metabolic products of
   CH2CHCH2OCH3?
4. If a person is exposed to a toxic substance over
   a short time period, how might the timeline of
   effects vary depending on a) compound polarity
   and b) toxicity of compound vs. metabolites?
5. Regulations often limit toxic substances through
   a) absolute concentration limits and b) time
   averaged concentration limits. Why would two
   separate limits be useful? What are the two
   limits protecting against?