Lecturer: Michelle M. Schaper, Ph.D.
I. Fundamental
concepts
A. Dose (concentration) - response
and time-response relationships
1.
What is meant by "dose"?
Paracelsus (1493-1541): "Sola
dosis facit venenum." (Latin)
(= "ONLY THE DOSE MAKES THE
POISON")
Any chemical, when administered in sufficient quantities, is capable of evoking adverse effects.
a. "Chemical":
toxicant or xenobiotic
b.
"Adverse": toxicology versus pharmacology
c. Definition: quantity (i.e.,
amount) of a chemical needed to produce an adverse effect(s) in a living
organism, generally reported
with a specified
period of time (e.g., 24 hours, 1 week)
d. Expression of dose
i. mg/kg (e.g., oral
or intraperitoneal exposure)
ii. mg/cm2
(e.g., dermal exposure)
e.
Range of dose: many orders of magnitude
The dose producing 50%
mortality of exposed animals is called the LD50. It is a
statistically-estimated value.
Example
LD50 values for dioxin
(10-3 mg/kg) vs. ferrous sulfate (103 mg/kg) or sodium
chloride
(104
mg/kg)
f. Inhaled chemicals
For these chemicals,
we typically discuss the exposure concentration (ppm or mg/m3).
This is not equivalent to
the dose; such a value does not tell us how much of the chemical
has entered the body.
However, it is possible to estimate the inhaled dose using equations that
incorporate the exposure
concentration along with minute ventilation, pulmonary retention,
length of exposure,
and body weight.
For airborne chemicals, the concentration producing 50% mortality of exposed
animals is called the LC50.
Like the LD50 value, the LC50 is a statistically-estimated
value.
Examples
Carbon
monoxide: 3,500 ppm (30 minutes)
Hydrogen cyanide: 170 ppm
(30 minutes)
2. What is meant by
"response"?
a. Definition: an
(adverse) effect(s) as induced by a chemical
b. Expression of response
i. Absolute units
ii. Unitless
(relative change)
c. Types of
responses: wide spectrum and range of values
Examples
Death/mortality/lethality: "alphabet soup" (i.e., A-Z)
Cancer: chromium VI* (gi,
lung), vinyl chloride (liver)
*Species importance
Eye and skin irritation:
sulfuric acid, sodium hydroxide
Respiratory irritation: acrolein and formaldehyde (upper
airway),
ozone and
phosgene (lower airway) Mutagenicity: tris, nitrous acid
Structural alerts: alkyl esters of phosphonic or sulfonic acids, aliphatic or aromatic nitro groups,
aromatic azo groups, aromatic ring
N-oxides, aromatic alkylamino or dialkylamino groups, alkyl hydrazines, alkyl
aldehydes, N-methylol derivatives, monohaloalkenes, nitrogen
and sulfur mustards, N-chloramines, propiolactones, propiosulfones, aliphatic and
aromatic aziridines,
aromatic and aliphatic substituted primary alkyl halides, carbamates, alkyl
N-nitrosamines, N-hydroxy and ester derivatives of aromatic amines,
aliphatic epoxides, aromatic oxides (Klaassen, 1996).
Sensitization:
anhydrides, isocyanates
Teratogenicity: cocaine, ethanol, thalidomide
3. How does time enter the picture?
a. Time is often
considered in toxicological studies. It is an important concern, but is secondary
to the issue of dose.
We must first know
how much of a chemical will produce a given effect (e.g., mortality). Then, we
can evaluate the rapidity
of the effect (e.g.,
minutes, days).
Example
Inhalation of approximately 1 or 10 mg/m3 of the herbicide, paraquat
(methyl viologen), will result in 100% mortality. At 10 mg/m3,
all animals will die
within 24 hours of exposure, but at 1 mg/m3, they will die within 72
hours.
b. Length of exposure
to a toxicant
i. Acute: under 1 day
(typically hours)
ii. Subacute: under 1
month
iii. Subchronic:
under 3 months
iv. Chronic: beyond 3
months
Note: A
rodent's lifespan is approximately 2 years.
c. Number of exposures
i. Single exposure
1) Repair
or recovery
ii. Repeated
exposure
1)
Cumulative effects
2)
Tolerance
4. Dose (concentration)
-response relationships
a. Premises
i. The
response(s) is/are indeed evoked by the chemical(s).
ii. The response(s)
is/are related to the dose (concentration); with larger doses (concentrations)
evoking larger responses.
iii. The response(s)
may be measured and quantified.
b. Types of dose-response
relationships
i. Graded individual:
response of an individual to varying doses (concentrations) of a chemical
ii. Quantal
population (*used extensively): distribution of responses to different doses
(concentrations) in a population of individuals
Figure 2. Example of
a quantal dose-response relationship (from Klaassen, 1996, page 21).
c. Features of dose
(concentration) - response relationships
i. Logarithm of dose
(concentration) versus response:
sigmoid
curve (i.e., "S-shaped")
1) Upper
portion of curve: low slope, plateau (i.e., hyposensitive or resistant)
2) Mid
portion of curve: linear range, greatest slope (i.e., most respond here)
3) Lower
portion of curve: low slope, plateau (i.e., hypersensitive or susceptible)
4)
Threshold: dose (concentration) where first get a response, estimate this point.
The $100,000 question: does a threshold exist for all chemicals?
ii. Dose
(concentration) - response relationships developed in laboratory studies (often
using animals)
a. Single
chemicals: real-world of mixtures
b. Single
exposure: real-world of repeated exposures
c. Higher
doses (concentrations) and extrapolate downward: real-world of low-level
exposures
d.
Typical relationship: three doses (concentrations) ---- low, medium, high
iii. Dose
(concentration) -response relationships developed in epidemiology or cluster
studies (often in workers)
a. No
exposure assessment
b. Length
of exposure unknown
c.
Numerous simultaneous exposures
d. Other
confounders: age, gender, race/ ethnicity, smoking
iv. Predictions
from dose (concentration)-response relationships: generally outside of the range
of data Examples
(Risk
Assessment) (see pp.40-44)
No
Adverse Effect Level (NOEL)
No
Observable Adverse Effect Level (NOAEL)
1 x
106 ("one in a million")
v. Comparisons from dose-response curves Relative potency: whole curve or point (e.g., 50%) comparisons
Examples
Acrolein is a more potent
upper airway irritant than acetone.
Parathion is a more
potent neurotoxicant than malathion.
Figure 3. Comparison
of relative potency (adapted from Lu, 1996, page 78).
5. Time-response relationships
Figure
4. Time-response relationship using respiratory frequency (f) for a group of 4
mice exposed to
50 mg/m3 ZnCL2
aerosol for a period of 3 hours. The soild line represents the mean response for
the group
of mice
and the dashed line represents 1 standard deviation above and below the mean
(from Schaper et al., 1995).
a Features of
a time-response relationship
i. Onset
of response
ii. Time
of maximum response
iii.
Sustained response for any period of time
iv.
Recovery from observed effect
b. Individual versus mean relationships
c.
Example
Exposure of mice to 50 mg/m3 ZnCl2 aerosol
(refer to Figure 4, above)
B. Portal(s) of entry and target and target organ(s)
1. Definitions
a. Portal of entry: site at which
a chemical enters the body
Examples
Respiratory tract : INHALATION
Skin : PERCUTANEOUS OR DERMAL
GI tract (gut) : INGESTION
Figure 5.
Environmentally-encountered chemicals enter the body through the lung (ie.,
respiratory tract),
through the
skin, and through the gastrointestinal tract.
b. Target organ(s): site(s) at which toxicity of a chemical is observed
*Note
that the target organ need not be the portal of entry.
Examples
Ingested paraquat (e.g., vegatation): lung
Ingested
cadmium (e.g., water): kidney and liver Inhaled n-hexane
(e.g.,
work, hobby): peripheral nervous system (PNS)
2. Ambient dose/concentration versus
tissue dose/concentration Exposure to a chemical does not necessarily result in
toxicity.
We must consider
the dose delivered to the target tissue.
C. Disposition of chemicals (Toxicokinetics)
Once a chemical enters the body, it may
be distributed to a variety of organ systems.
It is possible for the chemical to be
biotransformed and eliminated from the body, without production of adverse health
effects.
The fate and transport of
toxicants (and/or their metabolites) in the body may be monitored through the
evaluation of breath
(e.g., end-exhaled
air), blood (e.g., whole, serum, plasma, erythrocytes), and/or urine samples
collected from humans.
Such biological
monitoring or use of biomarkers is valuable for assessing environmental
exposures and it complements air sampling.
To properly conduct biological monitoring,
knowledge of the absorption, distribution, biotransformation, and elimination of
toxicants is essential.
Examples of
biological monitoring are given below.
Figure 6. Summary of
routes of absorption, distribution, and elimination of chemicals in and out of
the body (from Klaassen, 1996, page 91).
1. Absorption
a. Synonyms: uptake, entry
b. Definition: process by which chemicals are able to pass through body membranes and enter the bloodstream
c. Major routes of absorption
for environmental chemicals
i.
Inhalation (respiratory tract)
Examples
Gases:
carbon monoxide, nitrogen dioxide Vapors: carbon tetrachloride, chloroform
Aerosols: sulfuric acid mist, oil mist
ii. Dermal
(skin): also called percutaneous absorption
Examples
-
Airborne: aniline, methyl isocyanate (MIC), nitrobenzene, nitrogen
mustards
-
Solids: elemental mercury, zinc oxide ointment
-
Liquids: cyanide salt solutions (e.g., sodium cyanide), benzene, toluene
iii. Ingestion
(gastrointestinal tract)
Examples
-Water:
lead, iron (metals)
-Food:
organophosphates (pesticides)
-Accidental: acetaminophen, ethylene glycol (drugs, household products)
d. Other routes through which
chemicals may be absorbed (often used in laboratory-based animal studies)
i. Intravenous (IV)
ii.
Intraperitoneal (IP)
iii. Subcutaneous
(SC)
iv.
Intramuscular (IM)
v. Intradermal (ID)
e. Relative rate of
absorption:
IV >
Inhalation > IP > SC > IM > ID > Oral > Dermal
This helps us to
understand why the release of a chemical or biological agent into our atmosphere
(i.e., gas, vapor, aerosol)
can be so deadly.
f. Some factors affecting
absorption of a chemical
i. Age of the
exposed subject (or animal)
ii. Health status of
the exposed subject (or animal)
iii. Size of the
chemical
iv.
Diffusion limitations
v. Simultaneous
exposure to multiple chemicals
2. Distribution
a. Definition:
process by which chemicals are transported via the circulatory system to other
organs (beyond the portal of entry) and are passed into their composing
tissues
b. Some factors
affecting distribution of a chemical
i. Plasma protein
binding
ii. Extent of
perfusion (i.e., blood flow) through a given membrane
iii. Ease in
crossing cell membranes: diffusion or active transport
iv. Affinity for
tissues (oil/water partition coefficient)
c. Some special sites for
storage
i.
Plasma proteins (e.g., albumin and transferrin): metals (such as cadmium and
zinc), drugs (such as penicillin and salicylate)
ii. Liver: metals
(such as cadmium and zinc)
iii. Kidney: metals
(such as cadmium and zinc)
iv. Fat:
organochlorine pesticides (such as DDT and PCBs)
v. Bone: fluoride,
lead, and strontium compounds
d. Some special barriers to
chemical distribution
i. Blood-brain
barrier: methyl mercury, ethanol
ii. Placental
barrier: thalidomide, ethanol
Figure 7. Two
"special barriers" through which some chemicals may pass are:
the blood-brain
barrier and the placenta.
3. Biotransformation
a. Definition: process by which
chemicals are changed (metabolized), generally reducing their lipophilicity and
increasing their hydrophilicity
b. Some factors affecting
biotransformation of a chemical
i. Properties of the
chemical itself:
1)
Lipophilicity
2)
Binding (to proteins)
3)
Storage (accumulation)
ii. Role of the
living organism
1)
Species (human or animal)
2) Age
of exposed subject (or animal)
3)
Health status of exposed subject (or animal)
4)
Enzymes
a)
Types (genetic differences)
b)
Concentrations
c)
Inductibility
d)
Saturation
e)
Specificity
f)
Competition
g)
Number of chemicals to which exposed
c. Major organ involved in
biotransformation: liver
d.
Other organs involved in biotransformation: most tissues
| Lung | Skin | |
| LIVER | GI Tract | Gonads |
| Kidney | Placenta |
(adapted from Casarrett and Doull's Toxicology, 1991)
e. Major types of
biotransformation reactions
i. Phase I: add or
expose functional groups of the chemical, reactions involve microsomal mixed
function oxidases (MFOs),
cytochrome
P450s enzymes act as catalysts, reactions take place generally in the endoplasmic
reticulum of liver cells
Phase I
reactions
Oxidation, reduction, and/or hydrolysis
ii. Phase II:
congugate product of Phase I reactions to an endogenous molecule (to facilitate
elimination)
Phase II
reactions
Glucuronide
conjugation
Glutathione
conjugation
4. Elimination
a. Definition: process by which
chemicals (and/or their metabolites) are removed from the body
b. Major routes of elimination of
chemicals
i.
Urine (kidney)*
ii. Bile (liver)*
iii. Feces
(gastrointestinal tract)
iv. Air (lung)
c. Other routes
through which chemicals may be eliminated
i. Milk
ii. Secretions: sweat,
tears
iii. Hair
Example Methyl mercury ingested in contaminated bread, mercury levels monitored
in hair of Iraqi women
iv. Nails
d. Some factors affecting
elimination of a chemical
i. Age and health
status of exposed subject
ii. Size and
diffusion limitations of chemical
iii. Simultaneous
exposure to multiple chemicals
iv. Binding (to
proteins)
v.
Storage (bioaccumulation)
vi. Extent of
biotransformation
II. Environmental chemicals with important toxicological effects
A. Asphyxiants
1. Definition: chemicals that act within
the respiratory tract and circulatory system to produce oxygen deprivation,
may be life-threatening.
2. Classification of asphyxiants and
examples
a. "Simple"
asphyxiants
i.
Definition: chemicals that displace oxygen from inspired air, not biologically
active within the body, may pose fire
and/or
explosion hazards in the environment (particularly in closed spaces)
ii. Synonym:
chemicals producing arterial hypoxia
iii. Mechanism:
insufficient oxygen in the blood, insufficient oxygen bound to hemoglobin (Hb)
iv. Examples:
acetylene, argon, helium, methane
b. Chemical asphyxiants
i. Definition:
chemicals that interfere with oxygen transport in the blood or utilization by
tissues
ii.
Sub-classes
1)
Methemoglobinemia (MetHb) producers
a)
Mechanism: oxidation of iron in Hb, which results in disruption of oxygen
transport
b)
Reaction
Fe2+
<---> Fe3+ + 1e-
Occurs spontaneously, but less than 2% MetHb produced in normal individuals
c). Examples Aniline Nitrobenzene Sodium nitrite
2)
Anemic hypoxia producers
a)
Mechanism: chemical reacts with Hb, and displaces oxygen, oxygen transport
disrupted
b)
Reaction A + HbO2 AHb + O2
c) Example
Carbon monoxide (CO)
3)
Histotoxic hypoxia producers
a)
Mechanism: chemical reacts with cytochrome oxidase (aa3 or c) in cells, and
oxygen utilization disrupted
b)
Examples Hydrogen cyanide (HCN) Cyanide salts (Ca++, K+,
Na+)
B. Irritants (respiratory)
1. Definition: chemicals that act upon the
respiratory tract, potentially producing a wide variety of reactions
(e.g., burning sensation, cough,
constriction, inflammation) depending upon the level(s) of the respiratory tract
that is(are) reached
2. Major types of receptors involved in mediating responses to respiratory irritants
| Receptor/Nerves | Location | Primary Response |
|---|---|---|
| Trigeminal | Eye, nose, throat | Burning sensation |
| Arsenic | Larynx | Cough |
| Stretch, irritant | Trachea, bronchi |
Constriction of the conducting airways |
| Type J, C-Fiber | Alveoli | Rapid and shallow breathing |
3. Classification of irritants and examples
a. Sensory irritants
i. Definition:
chemicals acting at the nasal-pharnygeal region of the lung and upon the cornea
of the eyes, evoking a burning
(i.e.,
painful) sensation of the eyes, nose, and throat (thus, good warning properties)
ii. Synonyms:
upper airway irritants, upper respiratory tract irritants, lacrimators, mob or
crowd control agents
iii. Mechanism:
activation of trigeminal receptor
1)
Reaction with receptor (e.g, S-H groups of proteins)
2)
Physical adsorption to receptor
iv. Examples: Many,
if not most, industrially-used chemicals are capable of evoking sensory
irritation
1) Some
of the most potent (reactive chemicals: acrolein, chlorine, formaldehyde
(formalin), hydrogen fluoride, toluene diisocyanate
2) Some
of the least potent (non-reactive chemicals): acetone, methanol, toluene
b. Airways constrictors
i. Definition:
chemicals acting at the tracheal-bronchial region (i.e., directly or indirectly),
evoking constriction (i.e., painful),
may be
life-threatening
ii. Synonyms: mid airway irritants, mid respiratory tract irritants,
bronchoconstrictors, airway obstructors, airflow obstructors
iii. Mechanism: activation
of stretch receptor
1)
Direct
2)
Indirect: mediated by release of contents from mast cells (e.g., histamine,
prostaglandins)
iv.
Examples: anhydrides, isocyanates, house dust, mites, pollens, sulfuric acid mist
c. Pulmonary irritants
i. Definition:
chemicals acting at the alveolar region, evoking rapid shallow breathing, and
possibly inflammation which may lead to hemorrhage,
edema, and death (e.g., 24 hours post-exposure).
As environment, health, and safety professionals, it is extremely important for us
to identify those chemicals that have pulmonary irritating properties. In an accident,
pure pulmonary irritants will not provide a warning of their presence.
ii. Synonyms: lower airway
irritants, lower respiratory tract irritants, deep lung irritants
iii. Mechanism: activation of
juxta-capillary ("J")
receptors
1) Edema
(leakiness of blood-gas barrier) Initially, fluid moves into the space (i.e.,
interstitium) between the air sacs and the blood vessels.
Later, fluid may move into the air sacs, thus preventing proper gas exchange
(O2, CO2).
2)
Hemorrhage
iv. Examples:
ozone, phosgene, "chemical warfare" agents
C. Solvents (Vapors)
1. Definition: liquids which have the capability to be volatilized, often at standard temperature and pressure, used to solubilize another chemical (i.e., preparation of solutions)
2. General categories of organic
solvents
a. Alcohols R-OH
Examples: ethylene glycol, methanol
b. Aliphatics R-H There may also
be substitutions for the H (e.g, Cl, Br).
Examples:
carbon tetrachloride, n-hexane
c. Aldehydes, ketones R-CHO,
R-O-(C=O)-R
Examples: acetone, methyl ethyl ketone
d. Amines R-NH2
Examples:
aniline, ethylene diamine
e.
Aromatics Ar-H
Examples: benzene, toluene
f. Ethers, esters R-O-R,
R-O-(C=O)-R
Examples: ethylene glycol ether, methyl acetate
g. Miscellaneous
Examples:
CS2, mixtures (e.g., Stoddard solvent)
3. Human exposures
a.
Environmental
i. Air (e.g., industrial site releases)
ii. Water (e.g.,
drinking, showering)
iii. Soil (e.g., hazardous waste sites)
v. "Huffing" (common
among teenagers)
v.
Household products (e.g., nail polish remover, rubbing alcohol)
b. Occupational
4. Major routes of exposure
a. Inhalation: importance of
vapor pressure
b. Dermal:
importance of lipophilicity
c. Ingestion: importance of lipophilicity
5. Common complaints among individuals
exposed to solvents
a. Headache
b. Dizziness
c. Nausea
d. Sneezing
e. Fatigue
f. Eye irritation
g. Nose irritation
h. Nasal congestion
i. Dry or sore throat
j. Breathing difficulties (e.g.,
chest tightness, dyspnea)
6. Major types of toxicity induced by solvent
a. Acute effect
i. Central nervous system (CNS) (NEUROTOXICITY)
1.)
Narcosis: depression of the CNS which may lead to respiratory distress and
death
2.)
Acute toxic encephalopathy: degenerative brain disorder (particularly subthalmic
nucleus and pallidum), characterized by headaches, irritability, poor coordination, seizures and possibly,
coma and death
Example: carbon disulfide
ii. Kidney (NEPHROTOXICITY)
1.)
Necrosis
Examples : chloroform, ethylene gylcol
2.)
Acute renal disease
a.) Tubule damage: glomular, proximal
Examples: chloroform, carbon tetrachloride
b.) Acute renal failure
iii. Liver
(HEPATOTOXICITY)
1.)
Necrosis: zonal, organelle-specific, diffuse, massive
Examples: aniline, bromobenzene
2.)
Steatosis (fatty liver): accumulation of lipids
Examples: chloroform, carbon tetrachloride
3.)
Cholestasis: impaired production and/or secretion of bile
Example: toluene diamine
4.)
Hepatitis: (acute) inflammation of the liver
Example: halothane
iv. Respiratory (PNEUMOTOXICITY)
These
effects are concentration and time-dependent.
1.)
Sensory irritation: very common with solvents
2.)
Airways constriction
3.)
Pulmonary irritation
v. Skin
(DERMATOTOXICITY)
1.) Acute
irritant contact dermatitis: inflammatory state of the epidermis produced by
removal of protective fats, characterized by reddening, dryness, and itchiness (accounts for approximately
80% of all contact-related
dermatoses)
b. Chronic
effects
i.
Blood (HEMATOTOXICITY)
1.)
Leukemia
Example: benzene
ii. Central and
Periperal Nervous Systems (CNS, PNS)
1.)
Axonal/myelin degeneration: polyneuropathy Examples: n-hexane, methyl n-butyl
ketone (MNBK)
2.)
Chronic toxic encephalopathy: as described above for acute toxic encephalopathy,
but characterized by loss of memory,
lack
of motor control, dementia
Example:
carbon disulfide
3.)
Toxic Brain Syndrome (etiology not well-understood)
Example:
toluene
iii. Kidney
1.) Chronic renal disease (as described above for acute renal disease for solvents)
Examples: chloroform, carbon tetrachloride
2.) Cancer
Examples: benzidine, naphthylamine (1-, 2-)
iv. Liver
1)
Cirrhosis: fibrotic liver with impaired function
Example: ethanol
2)
Cancer
Example:
vinyl chloride
v. Skin
1)
Chronic irritant contact dermatitis (as described above for acute irritant
contact dermatitis for solvents)
7. Biological monitoring for exposure to solvents
a.
Trichloroethylene
i. Description:
chlorinated hydrocarbon (CHCl=CCl2), used for dry cleaning and
degreasing
ii.
Toxicity: possible narcosis, irritability, headache, and fatigue
iii. Fate of
trichloroethylene in the body
1.)
Unchanged (trichloroethylene itself)
2.)
Biotransformed
a.) Trichloroacetic acid (CCl3-COOH)
b.) Trichloroethanol (CCl3-CH2OH)
3.)
Determinants
a.) Breath (i.e., end-exhaled air)
b.) Blood
c.) Urine
b. Methylene
chloride
i.
Description: chlorinated hydrocarbon (CH2Cl2), used for
paint removal and degreasing
ii. Toxicity:
possible elevation of carboxyhemoglobin (COHb) levels; also a suspected human
carcinogen
iii.
Fate of methylene chloride in the body
1.)
Unchanged (methylene chloride itself)
2.)
Biotransformed
a.) CO
3.)
Determinants
a.) Breath (i.e., end-exhaled air)
b.) Blood
Figure 9. Carbon monoxide in exhaled air of workers exposed to methylene chloride.
Note the production, equilibration, and elimination of carbon monoxide which is an important metabolite of methylene chloride.
c. Some other examples
i. Aniline:
p-aminophenol in urine
ii. Benzene: phenol
in urine
iii. n-Hexane: 2,5
hexanedione in urine
iv. Toluene:
hippuric acid in urine
D. Metals
1. Definition: shiny, often solid chemical element
2. Some metals of
toxicological importance
a.)
"Essential" metals: cobalt, copper, iron, magnesium, manganese, zinc
b.) Heavy metals: arsenic,
cadmium, lead, mercury
Aluminum Copper mercury Arsenic Gold Nickel Beryllium Iron Selenium Cadmium Lead Silver Chromium Magnesium Vanadium Cobalt Manganese Zinc
3. Some anions with which metals may bond
a. Chloride (Cl)
b. Hydroxide (OH)
c. Oxide (O)
d. Sulfate (SO4)
4. Human exposures
a. Environmental
i. Air (e.g.,
releases from industrial sites)
ii. Water (e.g.,
drinking, showering)
iii. Soil (e.g.,
children eating dirt, hazardous waste sites)
iv. Hobbies (e.g.,
painting, ceramics)
b. Occupational
5. Major routes of exposure (importance of species)
a. Inhalation
b. Dermal
c. Gastrointestinal tract
6. Distribution of metals: bound to proteins such as albumin, ferritin, metallothionein
7. Major types of toxicity induced by metals
a. Acute effects
i. Central and
Peripheral Nervous Systems (CNS, PNS)
1) Acute
toxic encephalopathy (as described above for solvents)
Examples: lead, manganese
ii. Kidney
1)
Necrosis (as described above for solvents)
Examples: beryllium, manganese
2) Acute
renal disease
a)
Tubule damage: glomular, proximal Examples:cadmium, mercury
b)
Acute renal failure
iii. Liver
1)
Necrosis (as described above for solvents) Examples: arsenic, manganese
2)
Steatosis (as described above for solvents) Examples: arsenic, chromate
3)
Cholestasis (as described above for solvents) Example: manganese
iv. Respiratory
tract
1)
Pulmonary irritation Examples: cadmium chloride or zinc chloride fumes
2) Other
respiratory-related reactions
a)
Cough Examples: cadmium oxide, iron oxide
b)
Metal fume fever
Examples: cadmium oxide, lead oxide
b. Chronic effects
i. Central and
Peripheral Nervous Systems (CNS, PNS)
1)
Axonal/myelin degeneration (as described above for solvents)
Examples:
lead, mercury
2)
Chronic toxic encephalopathy (as described above for solvents)
Examples: arsenic, mercury
ii. Kidney
1)
Chronic renal disease (as described above for solvents)
Examples: cadmium, mercury
2)
Cancer
Examples: arsenic, nickel
iii. Liver
1) Cancer
Example: arsenic
iv. Respiratory tract
1)
Fibrosis: disease in which the lung is unable to expand properly, increased
collagen
Examples:
aluminum, beryllium
2) Cancer
Examples: cadmium, nickel
8. Biological monitoring for exposure
to metals
a. Some
examples
i.
Mercury
Figure 10.
Elimination of Hg in the hair of Iraqi women who ingested methyl mercury in
contaminated bread.
Note the slow
elimination of Hg following this exposure (from Clarkson, 1995, page 685S).
ii. Cadmium
iii. Lead
b. Determinants
i.
Blood
ii. Urine
E. Pesticides
1. Definition: biological, chemical or physical agent that is designed to kill plants or animals
2. General categories of pesticides
a. Insecticides: "bugs"
b. Fungicides: fungi (spores)
c. Rodenticides: rats, mice
d. Fumigants: agents that are
sprayed on öbugsä, fungi, seeds, nemotodes in soil, grains, fruit, and/or
vegetables
e. Herbicides:
plants
3. Specific classes of
pesticides
a.
Insecticides
i.
Organochlorines (now banned in the United States)
Examples: chlordane, DDT
ii.
Anticholinesterases
Examples: organophosphate esters, carbamate esters
iii.
Botanical-type
Examples: pyrethroids, rotenoids
b. Fungicides May be protective, curative, or eradicative Examples: hexachlorobenzene, organomercurials
c. Rodenticides Examples: norboramide, warfarin
d. Fumigants
Examples:
phosphine, ethylene dibromide
e. Herbicides
i. Chlorophenoxy
compounds
Examples: 2,4-D, 2,4,5-T
ii. Bipyridl
derivatives
Examples: diquat, paraquat
iii. Miscellaneous
Examples: acetanilides, triazines
4.
Human exposures: who is at risk
a. General population (e.g.,
meat/produce consumers)
b.
By-standers (e.g., living near orchards)
c. Workers (e.g., agricultural
workers such as ground applicators)
d. Poisonings (e.g., accidental
ingestion of rat poison, suicides)
5.
Major routes of exposure
a.
Inhalation
b. Dermal
c. Ingestion
6. Major types of toxicity induced by
pesticides
a. Acute
effects
i.
Blood
1)
Anticoagulation
Example:
warfarin
2)
Vasoconstriction
Example:
norboramide
ii.
Central and Peripheral Nervous Systems (CNS, PNS)
1) "SLUD"
syndrome: salivation, lacrimation, urination, defecation
a)
Mechanism: continuous stimulation of parasympathetic nervous system, no
cholinesterase to end neurotranmission
b)
Examples: anticholinesterases
2)
Tremors, seizures, convulsions
Examples: organochlorines, pyrethroids
3)
Muscular weakness
Examples: anticholinesterases
iii. Kidney and
liver
1)
Necrosis Examples: diquat, organomercurials, paraquat
iv. Respiratory
tract
1)
Pulmonary irritation Examples: ethylene dibromide, phosphine
2)
Respiratory arrest (paralysis of respiratory muscles)
Example: rotenoids
v. Skin
1)
Blisters
Example: hexachlorobenzene, Sarin (anticholinesterase)
2)
Chloracne
Example: Agent Orange (mix of 2,4-D and 2,4,5-T)
b. Chronic effects
i. Central and
Peripheral Nervous Systems (CNS, PNS)
1)
Organophosphate induced delayed neuropathy (OPIDN)
Examples:
organophosphates
2)
Psychopathic-neurologic lesions
Examples: organophosphates
ii. Kidney and
liver
1)
Cancer
Examples: acetanilides
7. Biological monitoring for exposure to pesticides
a. Some examples
(organophosphates)
i. Malathion
ii. Parathion
PARATHION
Specific metabolite: p-nitrophenol
Non-specific: cholinesterase activity in
red blood cells (< 70% of baseline)
iii. Triorthocresol phosphate (TOCP)
b.
Determinants
i.
Blood
ii. Urine
III. The Regulatory Arena
Environment, health and safety
professionals are often involved in: a) the development of exposure limits for
chemicals and b) litigation on
limits which have been established. Some of
the agencies and groups who propose exposure limits for chemicals used in the
United States
are given below.
A. National Exposure Limits (United States)
1.
Environmental Protection Agency (EPA)
National Ambient Air Quality Standards
(NAAQS)
"Cutting-Edge Research": PM
2.5
New Chemical Exposure Limit (NCEL)
2. Occupational Safety and Health
Administration (OSHA)
Permissible
Exposure Limit (PEL)
3. National
Institute of Occupational Safety and Health (NIOSH)
- Immediately
Dangerous to Life and Health (IDHL)
- Recommended
Exposure Limit (REL)
4. American
Conference of Governmental Industrial Hygienists (ACGIH)
Threshold Limit Value (TLV)
5. American Industrial Hygiene Association
(AIHA)
Workplace Environmental Exposure Level Guide
(WEEL)
Emergency Response Planning Guide (ERPG)
ERPG-1 to prevent mild
transient adverse health effects or perception of a clearly defined objectionable
odor
Example: 1 ppm
chlorine
ERPG-2 to
prevent irreversible or other serious health effects or symptoms that could
impair abilities to take protective action
Example: 3 ppm chlorine
ERPG-3 to prevent
life-threatening health effects
Example: 20 ppm chlorine
IV. Use of toxicological chemistry in risk assessment
A. Definition: Risk assessment is the systematic process for describingandquantifying the risks associated with hazardous substances, processes, actions, or events. (from Covello and Merkhofer, 1993)
1. Key words
a. Process: steps to be taken
b. Describing: qualitative
process
c. Quantifying:
quantitative process
B. Risk assessment paradigm: a four-step process
1. Hazard
identification: toxicology data important
2. Dose-response assessment: toxicology data
important
3. Exposure assessment
4. Risk characterization
Figure 12. Steps in conducting a
risk assessment (from NRC, 1983).
C. Interplay of risk-based activities
1. Risk characterization
2. Risk management: process by which policy
actions are taken to deal with the hazards identified in the risk assessment
process
3. Risk communication: process
of making the risk assessment and risk management understandable to the public,
etc.
D. Step one: hazard communication
Examining the chemical(s) of interest
1.
Molecular structure
2. Physico-chemical
properties
3. Toxicity
a. Known
i. Published human
reports (accidents, clinical data, epidemiology studies)
ii. Published animal
studies (bioassays)
b.
Unknown
i.
Modeling/predicting: QSAR
E. Step two:
dose-response assessment
1. Features of
dose-response relationships
a. Sigmoid shape
b. Threshold level
c. Plateau regions
d. Linear portion
e. Extrapolation
2. Use of the dose (concentration)-response
relationship
a. Dose: how
much of the chemical is involved?
b. Response: based upon the
amount of chemical that is involved, what type of effect(s) can we expect?
c. Statistical estimates that may
be needed in risk assessment
i. No Observable
Adverse Effect Level (NOAEL): in a subchronic toxicology study, this is the dose
at which no adverse effects are seen in the test animals
ii.
Lowest Observed Adverse Effect Level (LOAEL): in a subchronic toxicology study,
this is the smallest dose at which adverse effects are seen in the test animals
iii. Reference Dose
(RfD): daily dose that is assumed to be without adverse effects on the population
iv. Benchmark
Dose (BMD): 95% lower confidence bound on the dose producing a given level of
response (e.g., 10%)
v. Maximum Tolerated
Dose (MTD): in a subchronic toxicology study, this is the dose at which body
weight of the test animals is slightly suppressed (e.g., 10%)
vi.
LD50 (or LC50): in an acute study, this is the dose (or
concentration) that produces death (lethality) in 50% of the test animals (as
defined above)
F. Step three: exposure assessment
1. Data available
a. Exposure concentration
i. Air
ii. Water
iii. Soil
b. Exposure duration
c. Exposure frequency
2. Data unavailable
a. Modeling/predicting: fate and
transport
G. Step four: risk characterization
Ties the above
information together
1. Cancer risk:
10-4 to 10-6
2.
Noncancer risk: 1.0
H. Risk perception
1. Non-observable, uncontrollable
a. Electric fields
b. Nuclear reactor accidents
2. Non-observable, controllable
a. Microwave ovens
b. Diagnostic x-rays
3. Observable, controllable
a. Motorcycles
b. Fireworks
4. Observable, uncontrollable
a. Handguns
b. Auto accidents
Alarie, Y., Schaper, M., Nielsen, G.D., and Abraham, M.H. (1996). Estimating the sensory irritating potency of airborne nonreactive volatile organic chemicals and their mixtures. SAR and QSAR in Environ. Res. 5: 151-165
Alarie, Y. (1995). Lecture Notes from Organ Systems Toxicology course (EOH 2175)
Alarie, Y., and Luo, J.E. (1984). Sensory irritation by airborne chemicals: a basis to establish acceptable levels of exposure. In: Toxicology of the Nasal Passages (C.S. Barrow, ed.), Chemical Institute of Toxicology, Hemisphere Publishing Corporation, NY, pp.91-100
Alarie, Y. (1981). Toxicological evaluation of airborne chemical irritants and allergens using respiratory reflex reactions. In: Inhalation Toxicology (B.K.J. Leong, ed.), Ann Arbor Science Publishers, Ann Arbor, MI, pp.207-231
Alarie, Y., Kane, L., and Barrow, C.S. (1980). Sensory irritation: the use of an animal to establish acceptable exposure limits to airborne chemicals. In: Toxicology -- Principles and Practices (A.L. Reeves, ed.). John Wiley and Sons Publishers, NY, pp.48-92
Alarie, Y. (1973). Sensory irritation by airborne chemicals. CRC Crit. Rev. in Toxicol. 2: 299-363
Amdur, M.O., and Mead, J. (1958). Mechanics of breathing in unanesthetized guinea pigs. Am. J. Physiol. 192: 364-368
Amdur, M.O., and Mead, J. (1955). A method for studying the mechanical properties of the lungs of unanesthetized animals: application to the study of respiratory irritants. Proc. Inhal. Toxicol. Tech. Symp., Ann Arbor Science Publishers, Ann Arbor, MI, pp. 207-231
Amdur, M.O., Doull, J., and Klaassen, C.D. (editors) (1991). Casarett and Doull's Toxicology -- The Basic Science of Poisons. Fourth Edition. Pergamon Press, NY
American Conference of Governmental Industrial Hygienists (ACGIH) (1999). 1999 Threshold Limit Values for Chemical Substances and Physical Agents and Biological Exposure Indices. Cincinnati, OH, pp.1-185
American Conference of Governmental Industrial Hygienists (ACGIH) (1991). Documentation of the Threshold Limit Values and Biological Exposure Indices. Sixth Edition. Cincinnati, OH
American Industrial Hygiene Association (1999). Emergency Response Planning Guideline (ERPGs) and Workplace Environmental Exposure Level Guidelines (WEELs). Cincinnati, OH, pp.1-65
American Industrial Hygiene Association (1998). Syllabus from the 13th Annual Toxicology Symposium. Pittsburgh, PA
Clarkson, T.W. (1995). Environmental contaminants in the food chain. Am. J. Clin. Nut. 61: 682-686
Divencenzo, G.D., and Kaplan, C.J. (1981). Uptake, metabolism, and elimination of methylene chloride by humans. Toxicol. Appl. Pharmacol. 59: 130-140
Fulton, M., Thomson, G., and Hunter, R. (1987). Influence of blood lead on the ability and attainment of children in Edinburgh. Lancet 1: 1221-1226
Gilioti, R. (1994). EURONEST: a concerted action of the European community for the study of organic solvents neurotoxicity. In: Neurobehavioral Methods and Effects in Occupational and Environmental Health (S. Araki, ed.). Academic Press, NY, pp.23-32
Guyton, A.C. (1991). Textbook of Medical Physiology. Eighth Edition. W.B. Saunders Company Publsihers, Philadelphia, PA
Hartman, D.E., Hessl, S., and Tarcher, A.B. (1992). Neurobehavioral disorders (Chapter 14). In: Principles and Practice of Environmental Medicine (A.B. Tarcher, ed.). Plenum Medical Book Company, NY, pp.241-262
Hatzakis, A., Kokkevi, A., and Maravelias, C. (1989). Psychometric intelligence deficits in lead-exposed children. In: Lead Exposure and Child Development -- An International Assessment (M.A. Smith, L.D. Grant, and A.I. Sors, eds.), Kluwer Academic Publishers, Dordrecht, pp.211-223
Klaassen, C.D. (1996). Casarett and Doulls Toxicology -- The Basic Science of Poisons. Fifth Edition. McGraw-Hill, NY
Klaassen, C.D. (1994). Syllabus from the 1994 Mid-America Toxicology Course. Kansas City, KS
Lu, F.C. (1996). Basic Toxicology: Fundamentals, Target Organs, and Risk Assessment. 2nd ed. Hemisphere Publishing Corp., NY
Martini, M.K. (1996). Dermatotoxicology. Lecture Notes from EOH 2175 (Organ Systems Toxicology course), University of Pittsburgh, Pittsburgh, PA
Morrow, L.A., Steinhauer, S.R., Conray, R., and Dougherty, G.G. (1995). P300 latency prolongation in journeymen exposed to organic solvents. Abstracts from the Twenty-Third Annual Meeting, Seattle, WA
Morrow, L., Lederer, A., Steinhauer, S., and Conray, R. (1994). Occupational exposures to organic solvents: neurobehavioral effects. Abstracts from the Twenty-Second Annual Meeting, Cincinnati, OH
Morrow, L., Kamis, H., and Hodgson, M.J. (1993). Psychiatric symptomatology in persons with organic solvent exposure. J. Con. Clin. Psy. 61: 171-174
Morrow, L.A., Ryan, C.M., Hodgson, M.J., and Robin, N. (1991). Risk factors associated with persistence of neuropsychological deficits in persons with organic solvent exposure. J. Ner. Men. Dis. 179: 540-545
Morrow, L.A., Ryan, C.M., Hodgson, M.A., and Robin, N. (1990). Alterations in cognitive and psychological functioning after organic solvent exposure. J. Occup. Med. 32: 444-450
Muller, W.J. and Schaeffer, V. H. (1996). A strategy for the evaluation of sensory and pulmonary irritation due to chemical emissions from indoor sources. J. Air Waste Mgt. Assoc. 46: 808-812
Muller, W., and Black, M. (1995). Sensory irritation in mice exposed to emissions from indoor products. Am. Ind. Hyg. Assoc. J. 56: 794-803
National Institute of Occupational Safety and Health (NIOSH) (1997). Pocket Guide to Chemicals Hazards. Cincinnati, OH
National Safety Council (1996). Fundamentals of Industrial Hygiene (Fourth Edition). Chicago, IL
Needleman, H.L., Gunnoe, C., and Leviton, A. (1979). Deficits in psychologic and classroom performance of children with elevated dentine lead levels. N. Engl. J. Med. 300: 689-695
Rosenstock, L. And Cullen, M. (1986). Clinical Occupational Medicine. W.B. Sanders Co., Philadelphia, PA
Schaper, M.M. (1996). Lecture Notes from EOH 2175 (Organ Systems Toxicology course), University of Pittsburgh, Pittsburgh, PA
Schaper, M.M., Thompson, R.D., Boylstein, L.A., Luo, J.E., and Detwiler-Okabayashi, K.A. (1995). Use of a new computer program to detect the respiratory effects of zinc chloride (ZnCl2) aerosol in mice. The Toxicologist 15: 89
Schaper, M.M., Thompson, R.D., and Weil, C.S. (1994). Computer programs for calculation of median effective dose (LC50 or ED50) using the method of moving average interpolation. Arch. Toxicol. 68: 332-337
Schaper, M. (1993). Development of a database for sensory irritants and its use in establishing occupational exposure limits. Am. Ind. Hyg. Assoc. J. 54: 488-545
Stewart, R.D., Hake, C.L., and Peterson, J.E. (1974). Use of breath analysis to monitor trichloroethylene exposures. Arch. Env. Hlth. 29: 6-14
Stewart, R.D., Dodd, H.C., Gay, H.H., and Erley, D.S. (1970). Experimental human exposure to trichloroethylene. Arch. Env. Hlth. 20: 64-71
Taylor, G.M., Kramer, K.K., Klaassen, C.D., Detwiler-Okabayashi, K.A., and Schaper, M.M. (1995). Alteration of metallothionein (MT) levels in mice exposed to zinc chloride (ZnCl2) aerosol. The Toxicologist 15: 95
Vijayaraghavan, R., Schaper, M., Thompson, R., Stock, M.F., Boylstein, L.A., Luo, J.E., and Alarie, Y. (1994). Computer assisted recognition and quantitation of the effects of airborne chemicals acting at different levels of the respiratory tract in mice. Arch. Toxicol. 68: 490-499
Vijayaraghavan, R., Schaper, M., Thompson, R.D., Stock, M.F., and Alarie, Y. (1993). Characteristic modifications of the breathing pattern of mice to evaluate the effects of airborne chemicals. Arch. Toxicol. 67: 478-490
West, J.B. (1992). Pulmonary Pathophysiology -- The Essentials. Williams and Wilkins Publishers, Baltimore, MD
West, J.B. (1990). Respiratory Physiology -- The Essentials. Williams and Wilkins Publishers, Baltimore, MD
Williams, P.L. and Burson, J.L. (1985). Industrial Toxicology. Van Nostrand Reinhold, New York, NY
Environmental Chemistry Home Page
