Week 3: Toxicology, Genes, Genomics, and Environmental Health

Question 1

Define toxicology.

Answer 1

The study of adverse effects of chemicals on biological
systems

Question 2

What is the difference between a toxin and a toxicant?

Answer 2

A toxin has a natural origin and a toxicant is synthetic

Question 3

What important quote did Paracelcus say in the 1500s? How true is his statement

Answer 3

“The dose makes the poison”

Mostly true but some chemicals toxic at low doses, with no increase in toxicity at higher doses

Question 4

Identify the examples of different toxicity effects at the 7 levels of a human.

Answer 4

Molecule: DNA mutations due to radiation or chemical mutagen

Organelle: mitochondrial disruption due to pesticide exposure

Cell: cellular loss due to apoptosis from toxicant exposure

Functional unit: infertility due to damage to supportive Leydig cells in testes

Organ: renal failure due to heavy metal exposure

Body: weight loss due to impaired nutrient absorption in gut

Population: increased cancer incidence due to exposure to arsenic

Question 5

Define the dose-response curve.

Answer 5

A visual representation of the response rate of an individual/group/population through a range of doses of a particular substance (a toxin or therapeutic drug)

Question 6

Define ED-50 and TD-50. What should the relationship between them look like?

Answer 6

ED-50: effective dose 50%; the dose that causes an effect in 50% of the population of observed subjects
ED-50 of aspirin would be the dose that relieves headaches in 50% of the people

TD-50: toxic dose 50%; the dose that is toxic to 50% of the
population
Often used to indicate responses such as reduced enzyme activity, decreased reproductive success, or onset of specific symptoms

ED-50 should be much smaller than LD-50 or TD-50 and LD-50 and TD-50 should be as high as possible

Question 6

Give 3 details about the dose-response curve.

Answer 6

How individuals will respond to a chemical is not known

Instead predictions made about
how a percentage of the population will respond to a specific dose

Dose at which 50% of the population dies is LD-50 (lethal dose 50)

Question 7

Give () details about the dose-response curve regarding a particular chemical.

Answer 7

For a particular chemical, there may be a whole family of dose–response curves

Which dose is of interest depends on what is
being evaluated.

Overlap between the therapeutic dose (ED) and the toxic dose (TD); a slight increase in dose can have adverse effects

The greater the therapeutic index, the safer the drug

Question 8

Define the therapeutic index.

Answer 8

The ratio of the toxic dose 50% to the efficacy dose 50%

The larger the therapeutic index, the safer the drug

Question 8

Describe how timing and exposure can affect the dose-response relationship.

Answer 8

Can be influenced by timing and exposure route (adults vs fetus, oral vs dermal) and window of susceptibility

For a fetus, the primary exposure route is the placenta, which makes a fetus much more sensitive to toxic effects

For the route of administration, the the pesticide chlorpyrifos, an organophosphate is ten times more toxic via oral administration than via dermal application

Question 9

What is BPA? Why is it important?

Answer 9

BPA: organic chemical compound used as a building block for polycarbonate plastics, which are used in products like medical devices, reusable water bottles, and eyeglasses

People are exposed to BPA via 3 routes: oral, inhalation, and dermal

Oral is the most predominant route due to leaking into ingestible substances from containers

BPA levels in blood have been associated with a variety of conditions in women including obesity, endometrial hyperplasia, recurrent miscarriages, abnormal karyotypes, and polycystic ovarian syndrome

Question 10

What are the 3 classifications of toxicants?

Answer 10

Chemical class (heavy metals, alcohols, solvents)

Source of exposure (industrial pollutants, waterborne toxicants, and pesticides)

Effects on human health (hepatoxic and neurotoxic)

Question 11

Define environmental toxicology.

Answer 11

Studies toxicants that come from or are discharged into the
environment, and health effects on humans, animals, and ecosystems

Question 11

List the 6 types of toxicants and give examples of them.

Answer 11

Carcinogens: cause cancer Examples: radiation, benzene, nitrosamaine

Mutagens: cause mutations in DNA
Examples: radiation, bromine, benzene, ROS

Teratogens: cause birth defects Examples: alcohol, phenytoin

Allergens: cause unnecessary immune response

Neurotoxins: damage nervous system

Endocrine disruptors: interfere with hormones
Examples: DDT, dioxin, PCBs

Question 12

Why are animals studied in environmental toxicology?

Answer 12

Animals are studied for their own welfare and they act as “canaries in a coal mine” to warn of effects on humans

Question 13

Give an example of a teratogen. What mechanism does it use to affect the body?

Answer 13

The drug thalidomide, used
to relieve nausea during
pregnancy, turned out to be a
potent teratogen, and caused
thousands of birth defects
before being banned in the
1960s

It binds to guanine-rich sites in DNA

Question 13

Explain how chemicals can disrupt the endocrine system.

Answer 13

Some chemicals, once inside
the bloodstream, can “mimic”
hormones

If molecules of the chemical
bind to the sites intended for
hormone binding, they cause
an inappropriate response

Thus these chemicals disrupt
the endocrine (hormone)
system

Examples: DDT and the bird population; thyroid and PCB

Question 14

What routes can toxicants take through the environment?

Answer 14

Surface water and groundwater can accumulate toxicants

Runoff from large areas of land drains into water bodies, becoming concentrated

Toxicants in groundwater or surface water reservoirs used for drinking water pose potential risks to human health

Volatile chemicals can travel long distances on atmospheric currents

PCBs are carried thousands of miles from developed nations of the temperate zone up
to the Arctic, where they are found in tissues of polar bears and seals

Question 15

Give 3 details about persistence in chemicals.

Answer 15

Some chemicals are more stable than others, persisting for longer in the environment
Examples: DDT and PCBs

Temperature, moisture, sun exposure, etc., affect rate of
degradation

Most toxicants degrade into simpler breakdown products; some of these are also toxic

Question 16

Define and list the steps in toxicokinetics.

Answer 16

Toxicokinetics: the study of how a chemical is absorbed, distributed, metabolized, and excreted by the body

Absorption: chemicals gaining access to the inside of the body

Distribution: chemicals moving within your body to various organs

Metabolism: chemical processing facilitate elimination

Excretion: elimination from the body via urine, feces, and exhaled breath

Question 17

Give 5 details about absorption and distribution.

Answer 17

Solubility of a toxicant affects its absorption:
hydrophilic (water loving, polar) compounds are easily excreted in urine
hydrophobic (water hating, nonpolar) compounds can easily cross lipid-containing barriers (e.g., skin)

Hydrophobic (i.e., fat soluble) toxicants usually carried in
blood attached to proteins

Toxicants generally follow the laws of diffusion (move from higher to lower areas of concentration)

Chemicals absorbed in the intestine may undergo first-pass
metabolism in the liver

A few chemicals are excreted unchanged

Question 17

Give 4 details about metabolism.

Answer 17

Most biotransformation occurs in liver, rich in cytochrome p450 and other metabolic enzymes, but all cells have some capacity to metabolize xenobiotics

Biotransformations increase a molecule’s water
solubility/polarity, for easy excretion in urine

Four categories of metabolic transformations:
Oxidation (phase I reaction)
Reduction (phase I reaction)
Hydrolysis (phase I reaction)
Conjugation (phase II reaction; polar groups added to phase
I products)

Genetic polymorphisms and enzyme induction can both help explain why people react differently

Question 18

How can diet influence the condition of a disease?

Answer 18

The microbes in the intestine influence the uptake of chemicals and nutrients in the food and the chemicals to which we are exposed

They can alter the composition of the microbe’s stem cells and create a complex series of feedforward and feedback mechanisms that can have major effects

Question 19

Give 2 details about the factors that affect toxicity. What are the 2 types of toxicity?

Answer 19

Not all people are equal; sensitivity to toxicant can vary
with sex, age, weight, etc.

Babies, older people, or those in poor health are more
sensitive

Type of exposure:
Acute = high exposure in short period of time
Chronic = lower amounts over long period of time

Question 19

Give 3 details about mixtures of toxicants.

Answer 19

Substances may interact when combined together

Mix of toxicants may cause effects greater than the sum
of their individual effects.

These are called synergistic effects

Question 20

Give 4 details about the basic components of a gene and a genome.

Answer 20

DNA: 2 strings of bases (thymine, guanine, cytosine, adenine), with sugar (deoxyribose) attached to each, combined in double helix

Gene: specific sequence of nucleotides (base + its
sugar) controlling a cell function, e.g., make proteins

Human genome: ~3 billion base pairs/~24,000 genes; every cell has exact copy

Genes packaged in 46 chromosomes (each a matched
set of 2; 22 x 2 autosomes, plus 2 sex specific)

Question 20

What is the most common genetic variability? What are less common ones?

Answer 20

Most common: SNPs (single nucleotide polymorphisms): differences in single nucleotides in the same position of a gene

Less common: disease causing mutations, deletion polymorphism, gene duplication

Question 20

Give 4 details about excretion.

Answer 20

Major route is through kidneys/urine

Liver/bile also important for some chemicals

Volatile gases and vapors excreted primarily by
lungs, even if chemical originally absorbed by skin or ingested

Basic (e.g., high pH) and hydrophobic chemicals can be excreted through breast milk, posing unique risk for infants

Question 21

Give 2 details about liver cancer from moldy corn and peanuts.

Answer 21

In parts of Jiangsu province in China, liver cancer (hepatocellular
carcinoma, or HCC) was for many years the leading cause of death in males under the age of 50, yet in many other parts of the world, liver cancer in men is relatively rare

This population has a large number of hepatitis B cases and are constantly exposed to Aflatoxin B (occurs in moldy or contaminated foods)
GSTM1 deletion polymorphism is associated with about a twofold increase in risk of liver cancer

Question 22

How is gene expression regulated?

Answer 22

To initiate transcription, transcription factors (proteins) bind to a gene’s promoter region

Ligand-activated nuclear transcription factors need other
molecules, such as hormones, to bind first

Example: estrogen binds to the estrogen receptor, moves to
nucleus, binds to binding sites on the gene, turning it “on”

Endocrine disruptors are environmental chemicals that
interfere with this signaling

Question 23

Define epigenetics. Explain epigenetic regulation.

Answer 23

DNA methylation; in general:
Genes with more methylated bases in regulatory region
(hypermethylation) are underexpressed (switched off)
while hypomethylated genes are overexpressed (turned
on)

Interference during development can have lasting
effects; methylation changes also common in neoplasms

Other epigenetic mechanisms: histone
acetylation/deacetylation,

Epigenome responds to food, drugs, stress, toxicants

Epigenetic mechanisms likely responsible for most
environmental disease

Epigenetic information can be transmitted to offspring
(fetal origins of adult disease hypothesis)

Question 24

What are real world GxE examples?

Answer 24

Differences in drug responses between individuals (e.g., primaquine and hemolytic anemia in people
with G6PDH allele variant)
Black soldiers with the G6PDH allele variant contracted hemolytic anemia after using prophylactic cream

Acetylcholine, pseudocholinesterase and succinylcholine

Differences in alcohol responses (ALDH2*2 polymorphism = reduced ALDH2 enzyme function
and acetaldehyde buildup [flushing, hangover])

Question 25

Explain methylation and phenotype-importance of maternal diet.

Answer 25

All mammals have Agouti gene; gene product is a dual amino acid peptide that causes the pigment cells in hair follicles to produce a yellow pigment instead of brown/black

Agouti gene can also bind to certain receptors in the brain to change metabolism leading to obesity

When the Agouti gene has been demethylated (removal of methyl groups), the mouse is yellow, obese, and has a higher risk of diabetes and cancer

When the Agouti gene is methylated, the mouse is brown and healthy