Tox exam 2 Flashcards

A teratogen is a substance that can interfere with normal fetal development and cause congenital disabilities¹. Examples of teratogens include drugs, alcohol, chemicals, certain infections, and toxic substances¹.

Teratogens can cause abnormalities in a developing embryo or fetus when a person is exposed to or ingests them during pregnancy¹. The risk of damage from teratogen exposure during pregnancy depends on several factors, including the type of toxin, the duration of exposure, the amount of exposure, the gestational age of the fetus at exposure, and hereditary factors

Germ layers formed
Ectoderm→ skin and nervous system
Mesoderm→ bone, muscle, connective tissue
Endoderm→ linings of digestive and respiratory
system and other organs

Embryogenesis is a complex process that transforms a single cell into a fully formed organism. Here are the basic stages of embryogenesis:

1. Fertilization: A sperm cell fuses with an egg cell to form a single cell called a zygote^{1 2}.

1. Cleavage: The zygote undergoes rapid cell division, doubling in cell number with each round of division¹. This stage results in a 32-cell structure known as a morula¹.

1. Blastulation: The morula develops into a hollow ball of cells called a blastocyst^{1 3}. The blastocyst consists of an outer layer of cells (the trophoblast), an inner cell mass (the embryoblast), and a fluid-filled cavity (the blastocoel)¹.

1. Implantation: The blastocyst implants in the uterus⁴.

1. Gastrulation: The blastocyst develops into a gastrula, which has three germ layers: the ectoderm, mesoderm, and endoderm³.

1. Organogenesis: The germ layers develop into different organs and tissues³.
2. Growth and Differentiation: The embryo continues to grow and the cells continue to differentiate into more specific cell types².

mutations, chromosomal breaks, altered mitosis, altered
nucleic acid integrity or function, diminished supplies of precursors
or substrates, decreased energy supplies, altered membranes,
osmolar imbalance, enzyme inhibition, etc

The placenta
• The placenta plays a central role in transferring nutrients,
important hormones/peptides, and waste products between
the conceptus and mother
• The extent of the transfer depends on three major factors
• type of placentation
• physicochemical properties of the chemical
• rates of placental metabolism
• Most drug passage across the placenta seems to occur by
simple passive diffusion
• Lipid solubility, molecular weight, ionization
• Placenta toxicity can influence the metabolic “programming of
the fetus”
•Note: other maternal toxicity responses can affect the
developing fetus

The placenta is a temporary organ that develops in the uterus during pregnancy^{1 2}. It attaches to the wall of the uterus, and the baby’s umbilical cord arises from it¹. The placenta provides oxygen and nutrients to the growing baby and also removes waste products from the baby’s blood¹. It plays a significant role in fetal and adult health, and placental pathology is implicated in all common obstetric complications³.

The ability of a drug to pass through the placenta and reach the fetus is influenced by several factors^{4 3 5 6 7}:

1. Molecular weight: Drugs with a low molecular weight can more easily cross the placental barrier^{5 6 7}.
2. Lipid solubility: Drugs that are lipid-soluble can more readily diffuse across cell membranes, including the placental barrier^{4 6 7}.
3. Degree of ionization: Non-ionized drugs can more easily cross the placenta^{4 5}.
4. Protein binding: Drugs that are bound to proteins in the mother’s blood are less likely to cross the placenta⁷.
5. Concentration gradient: A higher concentration of a drug on the maternal side of the placenta compared to the fetal side can drive diffusion of the drug across the placenta^{4 5}.
6. Placental blood flow: The volume of blood perfusing the placenta can affect the rate of drug transfer^{4 5}.
7. Placental membrane characteristics: The physical properties of the placental membrane, including its surface area and thickness, can affect drug transfer^{4 5}.
8. Pathological changes in the placenta: Any pathological changes in the placenta can affect its ability to act as a barrier^{4 5}.

Air pollutants of major public health concern
•Particulate matter (PM)
•Carbon monoxide (CO)
•Nitrogen dioxide (NOX)
•Sulfur dioxide (SOX)
•Metals & metalloids (like lead)
•Green house gases (CO2)
•Hydrocarbons
•Volatile Organic Compounds (VOCs)
•Ozone (O3).

Anthropogenic Sources of Air Pollution:
• Fuel combustion e.g. motor vehicles
• Heat and power generation (e.g. oil and coal power plants and boilers)
• Industrial facilities (e.g. manufacturing factories, mines, and oil refineries)
• Residential cooking, heating, and lighting with polluting fuels
• Municipal and agricultural waste sites and waste incineration/burning
• Forest fires
• Natural sources
• Volcanoes
• Wildfires
• Windblown dust
• Natural biogenic vapors

EPA definition of Particulate Matter (PM): term
for a mixture of solid particles and liquid droplets
found in the air. Some particles, such as dust, dirt,
soot, or smoke, are large or dark enough to be
seen with the naked eye. Others are so small they
can only be detected using an electron
microscope.
• PM10 : inhalable particles, with diameters that
are generally 10 micrometers and smaller; and
• PM2.5 : fine inhalable particles, with diameters
that are generally 2.5 micrometers and smaller.

•Ozone, at concentrations that occur in urban areas, induces in
humans and experimental animals morphologic, functional,
immunologic, and biochemical alterations mostly in the lungs.
• O3 can irritate the lining of the nose, airways and lungs.
• Exposure to O3 can produce a variety of pulmonary function
changes
• i.e. chest pain and discomfort with breathing, pulmonary edema
• People with asthma might have more attacks and athletes might find it harder
to perform as well as usual.

• About 10 to 50 km above the Earth’s surface, UV light directly splits
molecular O2
into atomic O•, which then combines with O2
to form
O3
.
• Ozone layer: thin “permanent” barrier that absorbs
the short-wavelength UV light

Some sources of water pollution
◦ Sewage (waste water)
◦ Agricultural Pollution
◦ Oil/gasoline Pollution
◦ Radioactive Substances
◦ River dumping
◦ Industrial (e.g. mining, smelting)
◦ Pharmaceuticals & Personal Care Products (PPCPs)
◦ Water Disinfection By-Products

Consuming too much nitrate can
affect how blood carries oxygen and
can cause methemoglobinemia (blue
baby syndrome).
• Other symptoms connected to
methemoglobinemia include
decreased blood pressure, increased
heart rate, headaches, stomach
cramps, and vomiting.

Financial issues caused the state to decide to
cut back on the cost of water in Flint by using
local sources instead of buying water from
Detroit
• Lead levels were high: 15-30 μg/L, some
reports much higher than that
•. NO levels of lead are safe. The EPA has set a
max level (action level) of 15 μg.
• Flint River water was slightly more acidic than
the purchased water from Detroit. The water
ate away the protective layers in the pipes
• Adding phosphates

Pro: increasing health equity in
dental health

Con: Developmental neurotoxicity

Water is fluoridated to reduce tooth decay. Fluoride is a mineral that can strengthen tooth enamel, making it more resistant to decay^{1 2}. Many towns and cities add fluoride to their water supply because most water doesn’t have enough natural fluoride to prevent tooth decay³. The process of adjusting the amount of fluoride in a public water supply to a level known to make teeth stronger and more resistant to cavities is called water fluoridation².

However, there are potential harms associated with water fluoridation. Excessive fluoride can cause fluorosis, which is a defect in tooth enamel that ranges from barely noticeable white spots to staining and pitting⁴. Fluoride can also become concentrated in bone, stimulating bone cell growth, altering the tissue’s structure, and potentially weakening the skeleton^{4 5}. Moreover, there is a modest body of evidence suggesting that fluoride, at doses considerably higher than what’s generally in the water, might be harmful to human brains, particularly developing fetal brains⁶.

It’s important to note that the potential risks from consuming fluoridated water may outweigh the benefits for some individuals, especially in an era of fluoridated toothpastes and other consumer products that boost dental health⁴. Therefore, the use of fluoride should always be discussed with a healthcare provider to weigh the potential benefits and risks.

A group of chemicals that have been and
continue to be of significant environmental
concern
• Persistent in the environment
• Prone to long-range, global transport
• Bioaccumulate through the food web
• Toxic to living organism
• Associated adverse effects: disruption of the
endocrine, reproductive, and immune
systems, and potential ability to cause
behavioral problems, cancer, diabetes, and
thyroid problems.

Pesticides: any substance or mixture of substances intended for preventing,
destroying, repelling, or mitigating pests.
◦ Insecticides: insects
◦ Herbicides: weeds
◦ Fungicides: fungi and molds
◦ Rodenticides: rodents
Often formulations: active ingredient + other compounds to allow for mixing,
dilution, application, or stability

Herbicides
•Chemicals capable of killing or severely injuring plants
• Preplanting herbicides: applied to the soil before the crop is seeded
• Preemergent herbicides: applied to soil before the time of appearance of unwanted
vegestation
• Postemergent herbicides: applied to the soil after the germination of crop and/or weeds
• Contact herbicides: those that affect the plant that was treated
• Translocated herbicides: applied to the soil or above-ground parts of the plant that are
absorbed and circulated to distant tissues
• Nonselective herbicides: kill all vegetation
• Selective herbicides: kill weeds without harming the crops

Insecticides
•All chemical insecticides used today are
neurotoxicants
•As a class, insecticides have a higher acute
toxicity towards nontarget species compared to
other pesticides

DDT and Malaria
• DDT (Dichlorodiphenyltrichloroethane): an organochlorine insecticide
• DDT was introduced in 1942 as an insecticide
• DDT was banned in most countries by the mid 1970s because of adverse human
health and environmental effects
• It was banned in South Africa in 1996 (at the time ~10,000 cases of malaria
registered)
• By 2000, malaria cases reached 62,000
• After the reintroduction of DDT at the end of the year, the cases of malaria
were down to 12,500

DDT mechanism of action and toxicity
• Both in insects and in mammals, DDT interferes with the sodium channels in the
axonal membrane
• Acute exposure to high doses of DDT causes motor unrest, increased frequency
of spontaneous movements, abnormal susceptibility to fear, and
hypersusceptibility to external stimuli (light, touch, sound).
• Chronic exposure to DDT targets the liver: increase liver weight, cause hepatic
cell hypertrophy and necrosis, and potent inducers of CYPs. It also has been
shown to be endocrine-disrupting, have reproductive effects in both males and
females, and is classified as a probable carcinogen

Bacillus Thuringiensis
• Bacillus thuringiensis (Bt) is a soil microorganism that forms spores containing
protein crystals
• When insects eat the spores, toxins are proteolytically activated in the midgut
• The toxins create pores in epithelial cells, ultimately destroying them. The
insects die of gut paralysis
• The selective toxicity of Bt is attributed to the fact that crystalline Bt endotoxins
require activation by alkalis and/or digestion, conditions absent in the
mammalian stomach.
•Bt toxins have generally an unremarkable toxicological profile in mammals

• Glyphosate (N-phosphonomethyl glycine): one of
the most widely used herbicide in the world
• Inhibits 5-enolpyruvylshikimate-3-phosphate synthase,
which is responsible for the synthesis of an
intermediate in the biosynthesis of various amino acids
important in plant growth (not present in mammals)

Historical forensic toxicology
• Charles Norris was New York’s first appointed chief medical
examiner and Alexander Gettler was the head of his head
toxicologist
• The work of Norris and Gettler ultimately lead to the
widespread acceptance of science in crime investigations
• Arsenic, methanol, cyanide, morphine, lead, mercury, carbon
monoxide, radium

The toxicological investigation of a poison death may be divided into
three steps:

(1) obtaining the case history and suitable specimens,
(2) the toxicological analyses, and

(3) the interpretation of the
analytical findings.

Specimens of many different body fluids and organs are collected
(before embalming)
• Blood, urine, liver tissue, stomach contents
• Bone marrow, hair, nails, skeletal remains, vitreous humor of the eye, saliva,
sweat, amniotic fluid, breast milk, semen

For oral administration of poison
• GI content analysis: there may be large amounts of residual
poisons present
• Urine analysis: the kidney is a major organ of excretion for most
poisons
• Liver: after absorption from the GI track, things are carried to the
liver before entering systemic circulation

Initially: non-specific tests designed to determine the presence
or absence of a class or group
• Urine tests (like FPN color test)
• Examples of techniques used to isolate and identify the
compound
• Gas chromatography (GC)
• LC-MS
• High-resolution MS (TOP and Orbitrap)

• Biotransformation of the poison and normal chemical changes
that occur during the decomposition of a cadaver must be
considered
• During decomposition
• Phenylalanine → phenylethylamine (chemical and physical
properties similar to amphetamine)
• Hydrolysis/oxidation/reduction of proteins/lipids/nucleic acids
generate numerous compounds that may interfere with analysis

Forensic toxicologist are becoming more involved in the
analysis of specimens from living victims
• Administration of drugs to incapacitate→ kidnapping, robbery,
sexual assault
• benzodiazepines (Rohypnol), phenothiazines
• Poisoning as a form of child abuse
• Laxatives, diuretics, table salt, narcotics, antidepressants, sedative narcotics

1. Clinical stabilization of the patient
2. Clinical evaluation (history, physical, laboratory, and radiology)
3. Prevention of further toxicant absorption
4. Enhancement of toxicant elimination
5. Administration of antidote (if available)
6. Supportive care, close monitoring, and clinical follow-up

• Because of the limited clinical availability
of rapidly available “diagnostic” laboratory
tests for poisons, anion gap and osmol gap
calculations may be helpful diagnostic aids
(though measurements should be
interpreted cautiously)
• The AG is calculated as the difference
between the serum Na ion concentration and
the sum of the serum Cl and HCO3
ion concentrations. A normal AG is <12.

The osmol gap is calculated as the
difference between the measured serum
osmolality and the serum osmolarity
calculated from the clinical chemistry
measurements of the serum sodium ion,
glucose, and blood urea nitrogen (BUN)
concentrations. The normal osmol gap is <
10 mOsm.

Prevention of further poison absorption
• Preventing further absorption of a poison may be possible
if the exposure is oral, inhalation, or topical
•Inhalation: remove patient from exposure site into clean air with
proper ventilation
• Topical: remove contaminated clothing, gently wash skin with mild
soap (be careful not to cause abrasions that could enhance
absorption!)
•Oral (most effective ASAP): induction of vomiting, gastric lavage,
oral administration of activated charcoal, whole-bowel irrigation

Alkalinization of the urine: increase urinary filtrate pH to ionize
weak acids
• Hemodialysis
• Hemoperfusion
• Hemofiltration
• Plasma exchange or exchange transfusion
• Administration of activated charcoal serially

Use of antidotes in poisoning
• There are a relatively small number of specific antidotes
available for clinical use
• Practical difficulties in performing clinical research in poisoned patients
• Small financial incentive for commercial development
• The mechanisms of action of antidotes vary
• Physically bind to toxicant, preventing deleterious effect (e.g., chelating
agent for heavy metals)
• Opposite effect on a receptor (e.g., atropine vs organophosphate
insecticides)
• Chemical reaction that induces detoxifying capacity (e.g., sodium nitrate
and cyanide)

Antidote example: sodium nitrate and cyanide
• Cyanide binds to the ferric ions in cytochrome c oxidase
• When sodium nitrate is given to someone with cyanide poisoning, it
induces the formation of methemoglobin, which serves as an
alternative binding site for the cyanide ion. Cyanomethemoglobin is
then broken down in the body.
• Sodium thiosulfate acts as a sulfur donor in the conversion of
cyanide to thiocyanate, which is poorly retained in the mitochondria.

Occupational hierarchy for risk prevention
1. Substitution where hazardous chemical or activities are removed and
substituted with a safer chemical or process
2. Engineering controls that focus on reducing workplace exposures
3. Administrative controls that can be used to change job tasks or
methods
4. Use of PPE

Occupational Exposure Agents
Classified by IARC as Group 1
Definite Human Carcinogens

Evaluation of occupational risks
•In vitro assays
• Mechanistic insight
• Animal toxicology studies
• Adverse effect, mechanistic data, dose-response relationship
• Human challenge studies
• Verify animal toxicity studies, biotransformation pathways, rates of uptake and excretion,
threshold concentrations for response.
• Benefits balanced against risks
• Case reports
• Workplace surveillance or worker reports. These may lead animal or epidemiologic studies
• Epidemiology studies
• Unravel associations between occupational diseases, exposures, and personal risk factors

the protective ozone layer is in the earth's atmosphere at an altitude of about 6.2 miles. Free oxygen atoms will collide with one another and bind together

carbon monoxide will build up in blood. This forms carboxyhemoglobin (COhb). CO2 has a high affinity for red blood cells. When COhb increases carrying capacity decreases then tissue receives less O2

this can affect how blood carries oxygen and can cause methemoglobimia (blue baby syndrome)

can be taken up by food, medications, home products

the nitrate is converted to nitrite then it reacts with hemoglobin

Mass spec =mass to charge ration of ion. identifies/quantifies compounds based on unique mass spec. Liquid mass spec, gas mass spec (examples of this include ion exchange chromatography)

Gas chromatography = Vaporizes samples and passes then through a column with a carrier gas to sperate based on volatility. separates volatile and low weight compounds

liquid chromatography = dissolved un a liquid phase based on their interaction with the column's stationary phase. Nonvolatile substances

breathalyzer =measure blood alcohol concertation (ethanol)

Benefits = mechanistic insight, animal toxicology studies, does-response relations ship

limitations = not exactly human testing, overlooking of systematic effects, technical limitations

Benefits = verify animal toxicology studies, biotransformation pathways

limitations = ethical considerations

to prevent the release of metals in drinking water such as lead and copper

polyphosphates sequester iron and magnesium to prevent discolored water

reduces exposure to lead

1. Orthophosphate Treatment:
   • Purpose: Water systems add orthophosphate to drinking water to prevent lead pipes from leaching.
   • Reaction: When orthophosphate is added to the water, it reacts with lead to form a mineral-like crust inside lead pipes.
   • Protective Coating: This crust acts as a protective coating, preventing further lead corrosion and minimizing the release of lead into the water^{1 2}.

1. Solid Lead Phosphate Formation:
   • Mechanism: Orthophosphate reacts with lead and copper to create compounds that have a strong tendency to remain in solid form.
   • Stability: These lead phosphate compounds adhere to the pipe walls, reducing the dissolution of lead into the water.
   • Factors: The effectiveness of orthophosphate depends on its concentration, pH, dissolved inorganic carbon (DIC), and the characteristics of existing corrosion scale (e.g., presence of other metals like iron or aluminum)².

Organophosphate poisoning occurs after exposure to organophosphates (OPs), which are used as insecticides, medications, and nerve agents. Let’s delve into the mechanism of toxicity:

1. Inhibition of Acetylcholinesterase (AChE):
   • Key Mechanism: Organophosphates irreversibly inhibit the enzyme acetylcholinesterase (AChE).
   • Normal Function of AChE: AChE breaks down the neurotransmitter acetylcholine (ACh) at cholinergic synapses.
   • Consequence: Inhibition of AChE leads to accumulation of ACh in the body^{1 2}.
   • Result: Continuous stimulation of nicotinic and muscarinic acetylcholine receptors.
2. Cholinergic Crisis:
   • Central Nervous System Effects:
     • Overstimulation of nicotinic receptors: Anxiety, headache, convulsions, ataxia, and tremors.
     • Muscarinic overstimulation: Visual disturbances, chest tightness, wheezing, increased secretions, salivation, lacrimation, sweating, and urination.
   • Respiratory and Circulatory Depression:
     • Depressed respiration and circulation.
     • Potential coma and death³.
3. Status Epilepticus (SE):
   • Acute Exposure: Surge of ACh in cholinergic synapses.
   • Result: Peripheral cholinergic crisis or SE.
   • Severity: Can be lethal⁴.
4. Treatment:
   • Atropine: Blocks muscarinic receptors to counteract cholinergic effects.
   • Oximes (e.g., pralidoxime): Reactivate inhibited AChE.
   • Diazepam: Manages seizures.
   • General Measures: Oxygen, intravenous fluids, and supportive care^{1 2}.

Pros: stops malaria, is cheap

cons, can cause birth defects and other health issues such as cancer and abnormal childhood brain development

Cyanide disrupts cellar reparation by binding to cytochrome oxidase blocking intracellular reparation and increase lactic acid synthesis

treated by: Hydroxocobalamin in bind to or detoxify cyanide. can also use sodium nitrate.

Lung cancer when exposed to asbestos in a manufacturing building. This can cause asthma or COPD before the cancer is formed or caught.