Académique Documents
Professionnel Documents
Culture Documents
• Cesare, Lucretia
• Victims: husbands, wives, lovers, political opponents, clergy…
• Donizetti’s 1833 Opera “Lucrezia Borgia”
1
3. Catherine de Medici (1519-1589)
C. Age of Enlightenment:
2
Paracelcus’ Toxicological axioms:
D. Modern Era:
• 19th Century: analytical methods developed for poisons like As, Hg..
• Modern toxicology is multi-disciplinary, comprising scientists from
diverse fields, such as:
• biochemistry,
• molecular biology,
• engineering,
• epidemiology,
• chemistry,
• biology,
• genetics,
• microbiology,
• public health
• statistics
• pathology
• nutrition and food science, and others
3
II. Basic Principles Of Toxicology
dose
B. Response: assumptions...
4
KCN poison pills taken by prominent Nazis Hermann Goering and
Heinrich Himmler at the end of WWII.
2. Subacute: symptoms generally not as severe, but toxic effects often same
as acute ...
3. Chronic: progresses at a slow and varying rate; may be mistaken for other
diseases. Often difficult to determine cause-and-effect
5. Delayed Effects: effect may occur only after long exposure; agent cannot
be found in blood or tissues. Damage to system already done....radiation sickness
5
C. Dose and Effect: The dose-response curve,
D. Evaluating Dose-response:
1. For precision, dose-response curve usually plotted as log dose vs. % response....
2. Both are from the same experimental data, but log-dose scale results in a more
linear data representation..
3. the linear portion of the curve (~16 - 84%) is used to calculate toxic potency.
6
Here, LD50 = 100 mg/kg
⇐ Dose-response curve..
7
% response NED PROBIT
0.1 -3 2
2.3 -2 3
15.9 -1 4
50.0 0 5
84.1 +1 6
97.7 +2 7
99.9 +3 8
8
Comparable toxic potencies:
3. Margin of safety.....
9
5. Chemical interactions:
a. Addition.....
10
F. Target Organ Toxicity: many toxins do not produce general effects but are
specific to one or more tissues or organs......
• asbestos: mesothelioma
target organs are often not the site of the highest concentration of a chemical
• Lead concentrates in bone, but its effects are mainly seen in soft
tissues, such as liver, kidney and blood cells…
nitrosamines in liver
11
• Specific receptors and/or functions: toxicant may interact with
receptors in a given tissue....
• Physiologic sensitivity:
Study questions:
1. Describe how toxicology evolved into a modern science. Name some of the
persons who made significant contributions.
2. List and describe several sub-disciplines that are part of toxicology.
3. What is the single most important factor in chemical toxicity?
4. Define dose-response relationship. Sketch out a sample dose-response curve,
properly labeling the axes.
5. Define and compare acute, subacute, and chronic exposures and responses.
6. Does acute exposure necessarily result in acute response? Does a chronic
exposure necessarily result in a chronic response?
7. Define antagonism; what is the difference between functional, chemical,
receptor, dispositional antagonism?
8. Why do many chemicals affect certain target organs?
9. What is a probit transformation, and why is it used? Transform a log-dose
response curve to a log-dose probit curve.
10. How can we use the dose-response curve to describe potency, predictability
and various types of chemical interactions?
11. What is chemical synergism? Is it a common phenomenon? Give two examples.
12. What is a margin of safety? a therapeutic index?
12
III. DISPOSITION OF CHEMICALS IN THE BODY
subcutaneous
intramuscular
Gastrointestinal Lung
tract
Portal
Liver blood dermal
Blood and Lymph
Extracellular
fluid Fat
Bile
Feces secretion
Urine Expired s
air
13
A. ABSORPTION - The process by which toxicants cross body membranes and
enter the bloodstream
For a chemical to cause its effect, it must enter a cell. To enter a cell, it must
penetrate a biological membrane:
1. Biological membranes are primarily lipid – fatty acids. Non-polar, lipid soluble
compounds are therefore absorbed most efficiently.....
14
Rate and extent of absorption of hydrophobic chemicals depends on three
factors:
15
b. Molecular Size: small particles absorbed more readily than larger
pH of the environment,
16
consider the ionization of two compounds:
What is the theoretical proportion of sodium phenobarbital (pKa = 7.2) present in its
most lipid soluble form in the stomach (pH 2) and in the urine (pH 6.5)?
[HA] [HA] 5
pKa −pH = log ;7.2 −6.5 = 0.7 = log = = 80%
[A−] [A−] 1
17
€
3. Special transport
a. active transport:
b. carrier-mediated
c. endocytosis: pinocytosis/phagocytosis
• requires energy
a. percutaneous route
• wrapping of skin
18
b. Inhalation -- rapid absorption
19
• factors promoting absorption:
stomach contents
Plasma
concentration
of chemical
time
20
B. DISTRIBUTION -- Movement of chemical throughout the body….
the blood contains charged proteins to which chemicals will bind (eg.,
albumin, immune globulins, and transport proteins...)
b. fat storage
theoretical volume of fluid into which the total drug administered would have
to be diluted to produce the concentration in plasma
21
Vd of water soluble chemicals with a low Kow will be close to 3L or equal to that of
plasma water
examples:
Chlorpromazine (thorazine) Vd = 21 L
2. fecal excretion
3. pulmonary tract most important for gases and volatile drugs: benzene,
anesthetics, CCl4, toluene, methanol
22
D. BIOTRANSFORMATION
Absorbed chemicals are modified by the body to increase excretion and limit
toxicity
23
Cytochrome P450 (CYP). The most important enzyme in chemical metabolism –
normal function is steroidogenesis
a. Characteristics of P450
• hemoprotein (contains iron atom in active site), > 6000 genes; >2200 in
animals
b. CYP nomenclature:
CYP1A2
Family: Subfamily:
> 40% amino acid > 55% amino acid
sequence homology sequence homology
24
Human P450 Substrate specificity:
Chemical CYP
Benzo(a)pyrene, other PAHs 1A1
Aflatoxin B1, heterocyclic amines 1A2
Tobacco-specific nitrosamine (NNK) 2D6
Benzene, styrene, TCE, vinyl chloride 2E1
Nitropyrene, 6-aminochrysene, aflatoxin 3A4
B1
25
Codeine and P450 polymorphisms
26
PHASE I REACTIONS
27
2. Nitrogen hydroxylation:
28
4. Epoxidation:
5. De-sulfuration:
29
C. Hydrolysis reactions (add H2O to ester groups)
30
Epoxide hydrolase –important hydrolytic enzyme for environmental chemicals:
31
Carcinogenic products
from P450 metabolism
32
PHASE II REACTIONS
A. Sulfotransferase reactions:
• Enzyme: Sulfotransferase
• Coenzyme: Phoshoadenosine-
5'-Phosphosulfate
("PAPS")
B. Glucuronyl transferase
reactions:
33
C. Methyl transferase reactions:
• Enzyme: O-Methyltransferase
34
GSH conjugates then cleaved to cysteine derivatives in the kidney....
"SG" is usually the cysteine derivative of GSH; glutamate and glycine are
by-products.....
35
Enterohepatic circulation:
liver
stomach
Gall
bladder
Bile
duct
intestines Portal
vein
36
Study questions:
37
IV. TOXICITY TESTING AND RISK ASSESSMENT
Toxicity testing
Short-term genetic testing
Epidemiology
Low Dose estimation
Biological Monitoring
Risk Assessment and Risk Management
The Precautionary Principle
A. TOXICITY TESTING
• by mg/kg body weight: on a body weight basis, humans are generally 10-
times more susceptible than animals
38
2. Animal studies usually use high doses.
• a single dose
• goals:
• daily dose
39
3. Chronic toxicity tests:
• lifetime daily ingestion of toxicant in two species – rats (24 mo), mice (18
mo)
• dose selection: use maximum tolerated dose (that dose that slightly
suppresses body weight gain i.e., 10%) and fractions thereof
termination of experiment
4. Other tests
• reproductive effects
• inhalation toxicology
40
5. Short-Term Genetic Toxicology Assays
Because genetic assays detect Genotoxic Agents Only, some types of carcinogens
will not be detected.
41
A. Salmonella / Mammalian Microsome (Ames) Assay: Most widely-used predictive
assay:
b. rat liver fraction: ("S9 mix" contains liver enzymes and cofactors)
42
6. "Decision point" approach to results from Short and Long-term assays
A. structure of chemical
43
B. Epidemiology -- early detection and prevention of risk and the study of the
distribution and determinants of disease..
….or toxicology studies where they let the subjects (people) out of their cages…
disease?
exposure?
44
Three Types of Epidemiology Study Designs
science
45
2. A. Bradford Hill’s Criteria for Causation
a. Association is strong --- higher relative risks being more likely to indicate
cause…
Reading assignments:
2. Chort study: Doll and Hill. The Mortaility of Doctors in Relation to their
46
C. Low Dose Estimation
How do we extrapolate data from animal studies which typically use higher than
“real world” doses?
NOAELs generated from these low-dose models often form the basis of maximum
exposure limits called reference doses (RfD) or concentrations (RfC), or Acceptible
Daily Intakes (ADI), depending on the regulatory agency:
UF = uncertainty factor
47
These standards represent “safe” exposure limits that won’t result in an excess
incidence (usually > 1/106) of adverse health effects
Limitation of NOAELs:
Uncertainty factors (UF) take into account inherent uncertainty in interspecies (animal-
to-human) and intraspecies (human-to-human) extrapolations, as well as other
limitations:
BMD is modeled using the lower confidence limit for a dose at a specified
response level. Here, the BMDL of 8.3 µg/kg is determined from the 95%
confidence extrapolated from the dose-response curve fitted from
experimental data…
48
Uncertainty factors account for:
• Extrapolation: animal-to-human
• Extrapolation: human-to-human
• Experimental inadequacies:
10 10
interspecies
intraspecies
49
D. Risk and Hazard Assessment
The primary goal of toxicology is to assess risk posed by exposure to a toxic agent.
1. For risk assessment, a thorough knowledge of the terms hazard, safety, toxicity,
potency is essential:
• hazard: the probability that injury will result from a chemical under specific
conditions.
• safety: the practical certainty that injury will not result from use of a
substance
Since every compound is toxic to some degree, and nothing is totally harmless, the
conditions of use must be defined for an accurate assessment of risk ......
50
2. Perception of risk. Illustrated by “risk-space” diagram:
51
The Precautionary Principle: is a response to uncertainty, in the face of risks to
health or the environment. In general, it involves acting to avoid serious or
irreversible potential harm, despite lack of scientific certainty as to the
likelihood, magnitude, or causation of that harm. “Preponderance of evidence”
rather than scientific proof.
a. Environmental Chemicals:
b. Chemicals in Foods:
52
c. Occupational exposures:
OSHA sets only few industrial standards via in-house research and risk assessment,
called "Permissible Exposure Limits" (PELs)
• OSHA has adopted over 650 TLVs from this committee as PELs
• TLVs are generally lower than PELs for the same chemical
53
2. TLV-threshold limit value-short-term exposure limit (TLV-STEL)
3. TLV-ceiling (TLV-C)
E. BIOLOGICAL MONITORING
1. what is measured?
54
2. conditions for practical biological monitoring:
55
WHO guidelines on urine specimens:
F. REGULATORY TOXICOLOGY
56
2. regulations are modified as:
• worker “right-to-know”
• established NIOSH
57
c. Environmental Protection Agency
a. Toxic Release
Inventory:
(http://www.ep
a.gov/tri/)
58
2006 EPA TRI Data ; TRI Releases by State 2006
Study questions:
1. Explain how experimental data from animal studies are extrapolated to people.
2. What is the advantage of using an animal’s surface area as a dose criterion?
3. Why are high doses of chemicals used in animal studies?
4. Does a short-term acute animal study accurately predict all types of toxicity?
5. What is a carcinogen? Are all carcinogens “created equal”?
6. How are carcinogens ranked in the IARC classification scheme?
7. Explain how you would conduct an Ames assay, including all assay components.
8. Describe the process of risk assessment and risk management.
9. Identify and describe the three major types of epidemiology studies, and their
advantages and disadvantages.
10. What are the Hill’s Criteria for Causation?
11. Explain how data from animal studies are extrapolated to determine risk to “real
world” doses of chemicals people are typically exposed to.
12. What is a reference dose, and how is it calculated?
13. When is benchmark dose used to determine risk?
14. What is the difference between a reference dose, an acceptable daily intake and
a threshold limit value?
15. What are some factors that determine the uncertainty factor?
16. Define the “Precautionary Principle,” and explain its impact environmental
toxicology.
17. What is a biomarker? Give four examples of chemical biomarkers and explain how
they arise in the human body.
18. What is the TRI?
19. What is a PBT chemical, and why is it important?
59
V. CHEMICALS IN THE ENVIRONMENT
Topics:
• Chemodynamics—adsorption, evaporation
• Biomagnification
A. CHEMODYNAMICS
water and soil characteristics (water and soil are the ultimate sinks for all
chemicals)
60
1. ADSORPTION to soils: tendency of chemical to distribute among two phases, from
solution to soils...
chemical (adsorbate)
soil (adsorbent) water (solvent)
1. surface area
4. hydrophobic areas
1. Mineral fraction
Characteristics of clay:
4. hydrogen bonding
61
Two types:
Kaolinite: 2-layered alumino-silicate bilayer
-2
Silicon-Oxygen tetrahedron - Si2O5
-3
Aluminum Octahedron: Al(OH)6
62
B. Sand: not important in toxicant movement….
3. Hydrogen bonding
63
B. Chemical bonds resulting in adsorption (in clay or organic matter)
2. Hydrophobic bonding:
• Bases (cationic) bind to soil best: bind to cation exchange sites in clay
• Neutral compounds bind more easily than anionic species: aren’t repelled by
clay
64
Basic chemical (aniline)....
cationic species is more tightly bound than neutral species because it can bind with
cation exchange sites......
65
2. CHEMICAL EVAPORATION
a) Vapor pressure:
At 25 °C At 30 °C
Lindane 9.4 x 10-6 1.28 x 10-4
DDT 1.5 x 10-7 7.26 x 10-7
66
b). Vapor density do= PM/RT
Besides vapor pressure and vapor density, other factors affecting chemical
evaporation from soil:
1. concentration of chemical
67
2. temperature
3. Soil moisture
as soil becomes wet, compounds are displaced from binding sites and
evaporation increases....
4 . Soil type
68
B. Evaporation from Water
2. Ionization of compound:
69
B. Half-life of chemicals in biological systems:
time
time
70
4. When a chemical is constantly absorbed (zero-order) and eliminated (first
order), its kinetics in the body looks like this:
From the derivative dx/dt = k1-k2x, this equation defines the amount of chemical
at time t, with input (intake) and output (excretion) rates known. e = base of natural
logs = 2.178
at Xmax (plateau).....
then:
71
What is the maximum body burden of lead following a daily exposure (k1 ) to 2
-1
Xmax = 2mg day-1 /0.01 day = 200 mg
why multiply by 7?
By convention, seven half-lives are required to eliminate nearly all the chemical
or accumulate chemical to Xmax in the body:
How long does it take to reach plateau if the excretion rate doubles (i.e., now
0.02 day-1 ) at the same input rate?
if the input rate is three times original, (i.e., to 6 mg/day), what is the effect on
time-to-plateau and Xmax?
72
t0.5 = 0.693/0.01 = 69 x 7 = 485 days; tripling input has no effect on
time to-plateau
73
5. An illustration of this principle:
• Open a bank account with a plan to deposit $1 per day while withdrawing half of
your total balance each day
therefore:
1. What is the maximum balance ($ max) you can achieve in your account?
74
3. How long to deplete your account if you stop depositing?
C. BIOMAGNIFICATION
where concentration of chemical increases with organisms higher in the "food chain"
PARTICLE SURFACE
AREA (m2/g)
kaolinite clay 7-30
vermiculite 600-800
organic 500-800
matter
75
c. Kow of chemical
76
Results of study on concentration of PCBs in marine animals:
77
Chemical Kow and bioconcentration are closely correlated....
78
2. Artificial streams and ponds - Lotic Mesocosm:
Study questions:
1. Name four factors influencing chemical adsorption to soil. Name four factors
influencing chemical evaporation from water.
2. Why does a weak acid like the pesticide 2,4-D bind poorly to clay?
3. Calculate the theoretical proportion of the herbicide amitrole (pK = 3.0) that
would bind to kaolinite clay at pH 6.
4. Describe how the following chemical characteristics affects evaporation from
soil: vapor pressure, temperature, soil moisture and soil type.
5. Why aren’t chemicals with a low Kow biomagnified significantly?
6. How does a chemical’s H value affect its evaporation from water?
7. How is EM calculated, and how does it relate to chemical Kow ?
8. What is the Farm Pond, and how is it used to predict biomagnification?
9. What is the theoretical maximum body burden of lead assuming a constant
daily exposure of 0.02 mg, and a first order excretion rate of 10-4/day.
10. You are attempting to clean-up 5800 gallons of aniline on US Hwy 89, 5 miles
east of Logan. The majority of the spill is on the road shoulder adjacent to
the Logan River near the intake for the city’s water supply. Aniline (pK= 5) has
an appreciable vapor pressure. The soil on the spill site is a sand/clay mixture
(pH 6.5) but little organic matter; easterly (i.e., towards town) winds, warmer
temperatures and probable rain showers are forecast. In detail, a) what are
your immediate steps to reduce harm to people?; b) assess the
chemodynamics that will determine the movement of aniline from the
immediate site (consider all routes); c) detail the best course of action you
would take to contain the spill, to minimize the spread of contamination to the
local environment as well as to the inhabitants of Logan.
79
VI. Classes of Toxic Chemicals and Agents
2007 Comprehensive Environmental Response, Compensation, and Liability Act
(CERCLA or “Superfund”) Priority List Hazardous Substances
1. Frequency of occurrence
A. METALS
metal toxicity involves reactions with ligands that are essential for the normal
function of the system
80
Ligand: an anion and/or a molecule that contributes electrons to a metal.... bonds
range from strongly covalent to ionic...
the ligand binding ability of metals forms basis for some metal antidotes
81
1. ARSENIC (As) (not officially a metal, but a “metalloid”)
B. Disposition:
Arsenic (III) is the primary toxic form; Arsenic (V) [arsenate] is the most
prevalent
a. well absorbed through GI tract, lungs, skin,
b. accumulates in liver, kidneys, nails, bone, hair and skin
C. Toxicity:
acute toxicity (oral) : 120 mg causes 50-75% mortality in people
• burning and dryness of mouth, GI disturbances (diarrhea), projectile
vomiting
• capillary damage
• muscle spasms, coma due to extreme electrolyte loss
Chronic toxicity:
• difficult to distinguish from flu
• malaise, fatigue, GI disturbances, diarrhea or constipation, capillary
damage, renal damage (albuminuria), neuropathy, pale deposition bands on
82
ARSINE GAS (AsH3) – gas formed in metal manufacture; used in semiconductor
industry
• non-irritating, odor threshold 10x TLV( 0.05 ppm)
• most potent hemolyzer known (lyses red blood cells)
• between 10-60 ppm: symptoms after 30 min
• 250 ppm lethal in 30 min
• industrial exposure can cause skin and lung cancer
Arsenic – the King of Poisons, the Poison of Kings – Case studies: arsenic hot spots
2. BERYLLIUM (Be)
A. Sources: coal and combustion (steel and electric power industries), ceramic
industries, beryllium alloy manufacture, cigarette smoke. TLV-TWA= 2 µg/m3
of workroom air for an 8-hour work shift.
B.Disposition:
C. Toxicity:
• contact dermatitis most common toxicological effect—skin hypersensitivity
reaction
83
• chronic granulomatous disease “berylliosis;” “chronic beryllium disease (CBD):
cyanosis, shortness of breath, mottled lung on X-ray, alveolar
granulomas
3. CADMIUM (Cd)
A. Sources: electroplating, pigment for paints and plastics, cathode material for Ni-
Cad batteries, by-product of zinc and lead mining and smelting, "organ meats"
--liver and kidneys
B. Disposition:
Renal structure, Nephron and Renal Physiology and Mechanism of Renal Toxicity by
Metals
84
Case study: environmental disease caused by Cd pollution in Japan:
4. CHROMIUM (Cr)
A. Sources: plating, pigments, tanning salts, wood preservatives, fly ash; an essential
element-glucose and lipid metabolism – cofactor for insulin action
C. Toxicity: Cr+6 (chromate) is more toxic, the carcinogenic and mutagenic form of
chromium but less prevalent than Cr+3
• lung cancer.....
85
5. IRON (Fe)
A. Sources: diet and vitamins--body burden ca. 4 mg (67% as Hb, 27% bound to
ferritin)
C. Toxicity:
86
Free radical
mechanisms are
common in
toxicology
Oxygen-based radicals
like hydroxyl (OH.) are
common in toxicology.
Radicals react with
unsaturated (double bond)
fatty acid residues in cell
membranes resulting
hundreds of toxic
products, many of them
reactive toward protein
and DNA. 8-OH-dG is one
common mutagenic DNA
base.
Malondialdehyde (MDA),
an abundant product of
lipid peroxidation, reacts
with DNA to form
mutagenic adducts.
87
6. LEAD (Pb)
lead smelters, storage battery workers, painters and paint mfg, brick makers, cable
makers and splicers, galvanizers, miners, plumbers and pipe fitters, welders
Disposition: normal blood Pb: 17 µg/dl (17 µg/100 ml); > 30 µg indicative of exposure
muscle
88
Toxicity:
• few acute problems, primarily occupational hazard
• GI symptoms from oral exposure--"Painter’s colic" (persistent constipation)
• CNS toxicity: encephalopathy, headache, tremor, blindness
• hematologic toxicity: anemia due to decreased heme synthesis
• renal toxicity;
• possible human teratogen
• gum line (purplish line on gum margin) characteristic... “Burton’s Line”
7. MANGANESE (Mn)
Sources: steel alloys, dry-cell batteries, electrical coils, glass, dyes, welding rods.
Disposition:
• an essential element; homeostatically regulated absorption
• not systemically toxic; high oral doses can cause GI irritation
Toxicity:
most human effects from inhalation of manganese dioxide dust during mining or
manufacturing, resulting in acute or chronic effects:
89
8. MERCURY (Hg)
90
91
Hgo (elemental)—major risk is breathing vapors
• vapor absorbed via lung,
• if ingested, < 0.01% absorbed via GI
• can be oxidized to Hg+2 in vivo
• Hg+2 accumulates in kidneys after Hgo exposure
• more lipid soluble than inorganic forms:
• crosses blood-brain barrier: CNS toxicity -psychic, emotional symptoms
Hg+2 (mercuric)
• ~ 15% absorbed via GI tract causing GI disturbances
• selectively accumulated in kidney causing renal toxicity
• pink extremities, photophobia
92
Human Poisoning Case Studies:
93
9. NICKEL (Ni)
Ni(CO)4 --(nickel carbonyl) formed during Ni refining (reaction with CO) is most
Acute Toxicity:
94
10. THALLIUM (Tl)
Sources: pesticide bait (roaches, rats), fireworks, "color logs," optics, costume
jewelry, catalysts, alloys, semi-conductors, pigments, herbal supplements
Disposition: absorbed through the skin, lungs and GI tract; follows potassium
distribution (similar ionic radius to K)
Toxicity:
• has been used in murders (tasteless, works slowly)
• onset is 2-4 days
• Treatment: a) Prussian Blue – acts as ion exchange agent, sequesters Th,
increases excretion; b) dialysis
Symptoms of toxicity:
• extreme GI irritation; vomiting, cramps, etc
• myelin sheath toxicity causing: ascending paralysis, psychic disturbances,
"wrist-drop," abnormal reflexes
• acute alopecia (10-14 days after exposure)
• residues in hair, nails and bones
95
B. Air Pollutants, Gases, Vapors, Particulates, Fibers.
96
National Ambient Air Quality Standards (NAAQS) for the six “Criteria
Pollutants:”
http://www.epa.gov/air/criteria.html
(1)
Not to be exceeded more than once per year.
(2)
Due to a lack of evidence linking health problems to long-term exposure to coarse particle pollution,
the agency revoked the annual PM10 standard in 2006 (effective December 17, 2006).
(3)
Not to be exceeded more than once per year on average over 3 years.
(4)
To attain this standard, the 3-year average of the weighted annual mean PM2.5 concentrations from
single or multiple community-oriented monitors must not exceed 15.0 µg/m3.
(5)
To attain this standard, the 3-year average of the 98th percentile of 24-hour concentrations at each
population-oriented monitor within an area must not exceed 35 µg/m3 (effective December 17, 2006).
(6)
To attain this standard, the 3-year average of the fourth-highest daily maximum 8-hour average
ozone concentrations measured at each monitor within an area over each year must not exceed 0.08
ppm.
(7)
(a) The standard is attained when the expected number of days per calendar year with maximum
hourly average concentrations above 0.12 ppm is < 1, as determined by appendix H.
(b) As of June 15, 2005 EPA revoked the 1-hour ozone standard in all areas except the fourteen 8-hour
ozone nonattainment Early Action Compact (EAC) Areas.
97
Pulmonary anatomy and function: Overall organization....
98
The Inflammatory Response
Obstructive lung diseases (COPD, asbestosis, silicosis, etc.) and some lung cancers
have similar inflammatory pathology:
99
Monitoring health affects: Pulmonary function tested by spirometry:
PARAMETERS DEFINITION
respiratory rate frequency of breathing per minute
tidal volume volume of air exchanged per normal
breath
total lung capacity air volume in entire lung
vital capacity air volume exhaled by maximum
expiration following maximum
inspiration
compliance index of flexibility of the lung;
decreased compliance indicates
increased stiffness
Blood gases: PO2 PCO2 efficiency of gas exchange and index
of total alveolar ventilation...
100
inhalation of particles an occupational problem....
• grain dusts in agricultural workers
• silica and coal dust in miners
• metal dusts in foundry and smelting workers
0.8
Alveolar
Regional
deposition
0.4
Tracheobronchial
0.2
Particle diameter ( m)
101
1. Aldehydes
102
2. Acrolein (CH2==CHCOH)
Properties:
• unsaturated aldehyde, more irritating than formaldehyde
• major contributor to the irritating quality of cigarette smoke and smog
• combustion product of fuels and cellulose materials
• TLV-STEL=0.1 ppm
Toxicology:
• < 1 ppm: irritation of eyes and mucous membranes in sinus and respiratory tract.
• effects in exposed animals:
a. cilatoxic—decreased mucus clearance
b. increased tidal volume, respiratory frequency
c. vascular and myocardial toxicity
Mechanisms:
103
3. Formaldehyde (COH2)
Sources:
leather, wood and paper, resins, plastic and textile processes, funeral homes, pathology
and biology laboratories, particle board, carpet, upholstery materials, insulation (urea-
formaldehyde foam), disinfectants, cosmetics, deodorants, dyes, vehicle exhausts, tobacco
smoke, gas, oil, coal, wood, and rubbish incineration; photochemical smog; a normal
metabolite in cells
Properties:
• colorless gas; has a pungent odor extremely irritating to mucous membranes of eyes,
nose and throat.
• polymerizes readily-- sold and transported in solution or as polymer
• highly water-soluble; predominant as aqueous solution containing stabilizers (methanol
or methyl/ethyl cellulose). most common form is formalin (37% formaldehyde, 6 -
15% methanol).
Toxicology :
Acute:
104
Chronic:
• Cancer: animal studies indicate 6 to 15 ppm exposure for 2 yr induces nasal
squamous-cell carcinomas
• Probable human carcinogen
• chronic irritation of lung, possible contributor to "sick building syndrome”
(multiple, flu-like effects)
Sources: petroleum refining (by-product) decaying organic matter, pulp mills, volcanic
steam vents
Exposure limits:
1. TLV-TWA=10 ppm; STEL=15 ppm; 0.01%--irritation; 0.1% --collapse and death;
Toxicology:
105
5. Nitrogen Dioxide (NO2)
Sources: coal burning (coal contains < 6% S); steel smelters, other sulfur oxides (SOx)
106
Toxicology:
• soluble—mainly affects upper airways
• extreme irritant
• increased mucous secretion, loss of ciliated cells;
• bronchial constriction and increased pulmonary resistance;
• increased susceptibility to respiratory diseases
Sources and formation: photolysis of NO2 (from auto emissions), electrical arcs
O + O2 O3
NO + O3 NO2 + O2
107
Exposure limits: TLV-TWA: 0.05 ppm (heavy work); 0.08 ppm (moderate work); 0.1 (light
work)
Toxicology: a strong oxidizing agent and deep lung irritant affecting terminal bronchioles
and alveoli
Mechanisms of Toxicity:
108
8. Carbon Monoxide (CO)
Sources: automobile exhaust (20L CO min-1 hp-1)--Los Angeles air: 30-75 ppm; coal
burning, gasification, etc. (20-30% CO);
TLV-TWA: 25 ppm
50 20%
109
CO-HB in Signs and symptoms
Blood (%)
<2 No significant effects
2.5-4.0 Decreased short-term maximal exercise duration
in young healthy men
2.0 - 20.0 Decreased visual perception, hearing, motor and
sensorimotor performance, vigilance and other
measures of neurobehavioural performance
4.0-33.0 Decreased maximal oxygen consumption with
short-term strenuous exercise in young healthy
men
20-30 Throbbing headache
30-50 Shortness of breath, dizziness, nausea, weakness,
collapse, coma
> 50 Convulsions, unconsciousness, respiratory arrest,
death
Health Protection Agency
110
10. Urban Particulate Matter - PM2.5 , PM10
Sources: refineries, pulp mills, coal burning, wood burning, volcanism, transportation;
Properties: Diverse chemical makeup, include: SOx, NOx, organic compounds. Cache
• reduces visibility: absorbs UV light, and fine particles are the same
111
Epidemiology of PM:
Cache Valley has some of the highest urban PM2.5 measured in USA!
Two weeks during January – February 2004: highest PM2.5 -- 135 µg/m3 (EPA
monitor)
concentrates pollution;
112
6. formation of ammonium nitrate particles in atmosphere driven by
NH4NO3 formation
promoted by
temp RH
K
HNO3 + NH3 NH4NO3 (s,
(gas) (gas)
NO aq)
2 OH
N
O O
3
hydrocarbon NH
s 3
ureas
e
ure
a
113
11. Asbestos
Properties:
• a large group of naturally-occurring hydrated silicates that crystallize in a
fibrous pattern....
• asbestos is not dangerous until mined and processed, then becomes friable .
a) amphibole
114
characteristics:
b) Serpentine
• "curly"
• less potent than amphibole: more soluble and cleared from lung faster
Chrysotile Mg6Si4O10(OH)8
115
Asbestos Toxicology: Occupational diseases (all chronic)
Asbestosis
Lung cancer
specialists)
mines
116
High risk occupations to asbestos diseases:
• shortness of breath
“Amphibole hyphothesis”
• risk of cancer and other diseases thought to be more closely associated with
amphibole asbestos,
117
• Agency for Toxic Substances and Disease Registry (ATSDR—agency of
PHS)
o waste sites, unplanned releases, and other sources
118
12. Nanoparticles and Nanotoxicology
1. Examples of nanoparticles:
U of U Nanoinstitute
Australian study
119
C. Industrial solvents, vapors, and other chemicals
1. Benzene
Sources:
Exposure standards::
Biomarker: urinary phenol normal value: < 20 mg/g creatinine; tentative max
permissible: 45 mg/g
Toxicology:
120
Acute Toxicity:
• narcotic effects
Chronic toxicity: most critical to occupational risk: toxic to blood and blood-
forming cells
Causes appearance of immature, maturation arrested blood cells or
“Shift-to-the-Left”
121
PERIPHERAL
BLOOD
Erythrocytes Lymphocyte
Reticulo (RBCs) s
-cyte
Basophilic
Erythroblasts
STEM CELL
Erythro- POOL
cytes Juvenile
Megakaryocyte
Proerythroblast
Polychromatic Megakaryoblast
Erythroblasts
Myeloblast
Granular Platelets
Promyelocytes
Megakaryocyte
Granulocytic
Myelocytes
Granulocytic
Metamyelocyte Spent
BONE
Megakaryocyte MARROW
Adapted from Erslev and Gabuzda, Pathophysiology of Blood. W.B Saunders. 1975
122
2. Methyl tert-Butyl Ether (MTBE)
Sources/Uses:
Environmental Fate:
Human Exposures:
123
Toxicology of MTBE:
1. Acute:
• low animal and human toxicity (no effect: 5-50 ppm 2 hr exposures)
2. Chronic:
• polystyrene
• acrylonitrile-butadiene-styrene (ABS)
124
Exposure standards (styrene monomer): 30,000 workers in 1000 plants; >
300,000 exposed from styrene-containing products....
4. 1,3-butadiene (BD)
Uses: polymer component in synthetic rubber; 1997 production 1.7 x 106 tons (top
20 of synthetic chemicals)
125
Toxicology:
• Class A2 carcinogen
5. Vinyl Chloride
CH2==CH--Cl -CH2--CHCl—CH2--CH--Cl
Sources: plastics, water pipe, food wrap, phonograph records, aerosol propellants;
126
popularity due to low cost, resistance to corrosion, can be molded to any shape
Exposure to VC:
• consumer exposure from new homes, new cars, food packaging (peanut oil:
3 ppm)
Toxicology:
Mechanism of action:
127
6. Cyanide
Sources: fumigating products, gold and silver extraction, metal polishes, rat and
pest poisons, foods. Natural cyanogenic glycosides in foods
Disposition: cyanide gas well absorbed by all routes, but poisoning most
often following inhalation.....
Toxicology:
• exceptionally toxic, and rapidly acting...
• brain primary target organ
• characteristic bitter, almond-like odor and taste...
Symptoms:
• rapid onset if inhaled (1-2 seconds..); symptoms following ingestion of
128
7. Methylisocyanate CH3N=C=O
Properties:
• boiling point= 39°C, vapor pressure= 348 mm Hg
• poor "warning properties"
a. human thresholds for odor detection (> 2 ppm) and mucous
membrane irritation (> 0.4 ppm) are greater than the TLV (0.02
ppm)
Toxicology:
• short half-life in body:
• < 2 min contact irritant to mucous membranes and respiratory tract
• initial injury confined to areas of direct contact (eyes, lungs)
• lasting lung damage may result from exposure--pulmonary congestion, cell
death
129
Acute effects:
• severe irritation of eyes, nose, throat, cough, choking sensation
Chronic effects:
• pulmonary hypertension
130
D. Aromatic and Low Molecular Weight Halogenated Hydrocarbons
trihalomethanes, trichlorethylene
Sources: cooling and insulating fluids for transformers and capacitors; hydraulics,
plasticizers, waxes, carbonless paper; banned in US 1977....
131
• Toxic
GE: Largest Superfund site in USA: 1947-1977 1.3 million pounds dumped into
Hudson River
B. Triclosan
132
C. Chlorophenols
Sources, uses:
Toxicology:
• immunotoxin
D. 2,3,7,8-tetrachlorodibenzo-p-dioxin ("dioxin;TCDD)
133
Sources of TCDD:
• soil contaminant (Times Beach, MO); tightly bound to soils, thus, not a
134
purple stools, urine, abdominal pain, vomiting, neuropathy, seizures,
• immunotoxicity
• cancer
135
• gene repressor is lifted off by TCDD-receptor complex
• results in P-450 induction, TCDD metabolism, widespread toxicity.....
Seveso Italy (1976): Reactor explosion at Icmesa Chemical Co.; Chloracne major
human toxicity following large release of TCDD . Serum TCDD among highest
recorded.
Times Beach, MO (1971): waste oil containing TCDD sprayed on road for dust
A. Trihalomethanes
136
Sources::
B. 1,1,2-Trichloroethylene (TCE)
Sources:
Environmental Chemodynamics:
Toxicology:
137
C. Polycyclic Aromatic Hydrocarbons and Aromatic Amines
138
other PAHs (all are carcinogenic)
139
Toxicology and Metabolism:
140
D. Xenoestrogens (or “Endocrine Disruptors”): a foreign (Gr. xeno)
compound with estrogen-like properties
141
Proven Xenoestrogens
142
Link between xenoestrogens and reproductive effects in wildlife?
• Alligators developed altered hormone levels, small reproductive organs and other
anomalies following a Kelthane spill in 1980, a pesticide with DDT as contaminant
Xenoestrogens and other tumor promoters are carcinogenic, but they act in the
“promotion” stage in carcinogenesis.
143
E. Pesticides
• insecticides
• herbicides
• rodenticides
• fungicides
I. INSECTICIDES
144
1. DDT
145
TOXICOLOGY OF DDT (in animals):
2. METHOXYCHLOR
• no biomagnification
3. DICOFOL (Kelthane® )
cotton
• Soil residues decrease rapidly, but traces remain for > 1 year
146
B. CHLORINATED CYCLODIENES
Toxicology:
• biotransformed to epoxides
ACUTE CHRONIC
dizziness, headache psychological disorders
nausea, vomiting intermittent twitching
clonic (thrashing) and tonic (tetani) convulsions
convulsions
effects eventually subside due to Hepatoxic, carcinogenic
redistribution into fat
147
148
C. LINDANE
TOXICOLOGY:
ACUTE CHRONIC
CNS toxicant--more violent blood disorders -- leukemia
convulsions than DDT
Hepatotoxic, carcinogenic
D. ORGANOPHOSPHATES:
1. Types
• no metabolism required
149
B. Insecticides
• require bioactivation
2. Characteristics:
150
3. Toxicology:
c. salivation, sweating
d. bradycardia
e. tremors, twitching
g. cyanosis, apnea
h. convulsions, death
151
Autonomic nervous system Central N. S.
Parasympathetic Sympathetic Somatic
*Classification of nerves by transmitter or mediator released and location of cell body Adapted from Selkurt
Physiology
and synapse; + = stimulatory - = inhibitory. Ach = acetylcholine; NE = norepinephrine; Epi
Little, Brown and Co. 1976.
= epinephrine
152
4. Mechanism of Toxicity: irreversible covalent phosphorylation of the serine
active site of the acetylcholine esterase (AChE) enzyme.....
153
5. Treatment of Organophosphate Poisoning: exposure to OPs is life threatening,
but specific dual antidote therapy is effective
154
MALATHION
• less hazardous
• widely used
AZINPHOS-METHYL (GUTHION)
TRI-O-TOLYL-PHOSPHATE (TOTP)
155
E. Carbamates
156
Carbamate toxicology:
Diflubenzuron (Dimilin)
Mormon Crickets
157
F. BOTANICAL INSECTICIDES
Pyrethrins
• flowers are imported from Kenya, Rwanda, Tanzania and Ecuador (0.9-
1.3% pyrethrins)
Mechanism of action:
158
II. HERBICIDES
A. Chlorophenoxy herbicides
1. Characteristics:
• acids pKa = 3
• water soluble
2. Toxicology:
159
B. Bipyridyl herbicides
1. Uses:
2. Characteristics:
• highly polar (charged), poorly absorbed through skin and G.I. tract
3. Toxicology of paraquat
160
4. Pathogenesis of paraquat exposure: (regardless of route of exposure)
• labored breathing
• convulsions
C. TRIAZINES
1. Uses:
2. Toxicology
161
III. RODENTICIDES
A. STRYCHNINE
1. Historical uses:
• once popular for rodent and pest control (U.S.); bear poison (Japan)....
2. Use today:
2. Symptoms of poisoning:
3. Treatment
162
• potassium permanganate (KMnO4) 1:5000-10,000 dilution to oxidize
strychnine
B. WARFARIN (COUMADIN)
Study questions
1. What was the first antidote specific for metals? How does it work?
2. What is the criteria used by the EPA for their CERCLA list of priority
pollutants?
3. Why does arsenic top the EPA’s CERCLA list of priority pollutants?
4. What is the mechanism of action of iron toxicity?
5. Arsenic contamination in drinking water is particularly high in Eureka and
Park City, UT. What is its likely source?
6. Lead is one of the first metals discovered to be poisonous. Describe how
lead is toxic to the CNS and to the blood system.
7. Identify real-life episodes involving poisoning by Cd and Hg
8. Is all mercury alike toxicologically?
9. High concentrations of Hg have been found in Utah trout. What is its
likely source, and why is it a health concern?
163
10. re some properties of Th that have made it a popular poison for murders?
11. Describe the mechanism by which CO is toxic, and the physiological
sensitivity that makes it so.
12. How is pulmonary function measured? How would they change after
exposure to acrolein, H2S, and ozone?
13. What is PM2.5, and how does it impact human health?
14. How is Cache Valley PM2.5 formed, and what are some possible solutions?
15. Describe how benzene acts both acutely and chronically. Identify some
clinical signs of chronic benzene toxicity.
16. Both CN and ethyl parathion have two-stage antidote therapies. Compare
and contrast.
17. Are all forms of asbestos of equal toxic potency? Explain.
18. Describe the mechanism of action of TCDD toxicity. How is it similar to
some xenoestrogens?
19. Describe the multi-stage model of carcinogenesis.
20. Identify two instances of human poisoning with TCDD.
21. Why is TCE a commonly-found contaminant in drinking water in urban
areas?
22. What was the first chemical carcinogen identified? How made the
discovery?
23. What is a Bay-Region, and why is it important?
24. Describe the bioactivation of benzo-α-pyrene.
25. What are some of the major reasons that the sale and use of DDT was
banned in this country.
26. What are some of the similarities and differences between nerve gases
and organophosphate insecticides?
27. Describe the antidotes used for organophosphate poisoning and their
mechanism of action.
28. Define and give three examples of a xenoestrogen. Why are
xenoestrogens important toxicologically?
164