Toxicology Exam 2

Ultimate Toxicant

Chemical that reacts with endogenous target molecule (DNA, proteins, lipids, etc.) and alters biological environment → toxicity

Pre-systemic (First-pass) Elimination

Toxicants may be eliminated before systemic circulation (opposite to absorption)

First metabolism by the liver may eliminate toxicants absorbed by the GI tract before they reach circulation

Give an example of a mechanism facilitating distribution toward a toxicant’s target site

More porous capillary endothelium increases distribution of toxicant → target

Give examples of mechanisms opposing distribution toward a toxicant’s target site.

Toxicant binding to plasma proteins decreases distribution

Specialized barriers (placenta protects fetus, blood-testis barrier, blood-brain barrier) decrease distribution

List and describe the elimination systems for hydrophilic and hydrophobic compounds

Liver/kidneys effectively remove hydrophilic compounds

The body metabolizes hydrophobic compounds → hydrophilic compounds to effectively remove (mammary gland, bile, exhalation, → intestinal lumen from blood - not very effective at removing hydrophobic)

Reabsorption

Toxicants can take advantage (diffuse across tubular cells → capillaries) and prevent elimination

Explain the relationship between a toxicant’s hydrophobicity/hydrophilicity, tubular reabsorption, and elimination

↑ hydrophilicity = ↓ reabsorption = ↑ elimination

↑ hydrophobicity = ↑ reabsorption = ↓ elimination

Easier to reabsorb hydrophobic molecules b/c they are not effectively eliminated

Reabsorption vs elimination (inverse) 

Biotransformation

A reaction where the original compound is transformed by an enzyme to form a new product

Toxication

Biotransformation to a more harmful product → more reactive (interacts more effectively within the body)

Detoxication

Biotransformation that prevents formation of or eliminates the ultimate toxicant

List the three types of macromolecules that are most often targets for toxicants

1. Proteins (enzymes, proteins)

2. DNA

3. Lipids (membranes)

Give examples of the general ways by which toxicants can cause target molecule dysfunction and destruction

1. Dysfunction: Enzyme/receptor inhibition & binding to transcription regulator proteins in the nucleus

2. Destruction: Lipid peroxidation (destroying lipids) & DNA radiation damage

List and describe the objectives of risk assessment

1. Putting environmental issues into public health and/or ecological context

2. Engaging stakeholders (people bearing the risk, corporations, government, scientists)

List and briefly describe the four primary methods for assessing toxicity of chemicals

1. Structure Activity Relationships (SARs) - Allows you to predict toxicity based on structure/chemical properties (cheaper alternative)

2. In Vitro/Short-term tests - Lab experiments/outside of body (bacterial mutation assays, neurotoxicity, reproduction, etc.)

3. Animal Bioassays - Reflects precautionary principle (chemicals that cause tumors in animals → humans) + dose response curve in animals must be adjusted to lower risk estimates for humans

4. Epidemiological Data - Gives the best evidence for human risk assessment (affected by lifestyle factors/biological variability)

NOAEL

“No Observed Adverse Effect Level”

Highest non-statistically significant dose tested

LOAEL

“Lowest Observed Adverse Effect Level”

Lowest dose tested with a statistically significant effect

Reference Dose (RfD) or Acceptable Daily Intake (ADI)

Estimate of safe levels of exposure

RfD/ADI = NOAEL / UF x MF

Uncertainty Factors (UF) and Modifying Factors (MF)

Always factors of 10

UF = 100 used in RfD calculations to generalize between animal → human studies (if human experiment only need 10)

MF = 10 used to adjust UFS if data on pharmacokinetics/relevance of animal response are available (mice absorb differently)

Variation of Susceptibility

Age, gender, health status, lifestyle, diet, medications, etc. can affect how vulnerable an individual/pop. is to exposure levels

Besides biological and toxicological data, explain the other factors that must be considered when making risk assessment decisions

Diverse statutes for making risk management decisions (can consider risk only or balance risk and benefits)

Must consider biological/toxicological data, public/media attitudes, individual behaviors, social risk attitudes, social risk factors

Fibrosis

Excessive deposition (formation) of abnormal extracellular matrix (scarring of tissue)

Inappropriate repair mechanisms

Carcinogenesis

Involves inappropriate function of repair mechanisms → cancer

Apoptosis

An active deletion of damaged cells (cells are destroyed in a controlled manner for replacement)

Requires energy

Proliferation

Regeneration of tissue (replacement of lost cells through mitosis & replacement of extracellular matrix)

Dysregulation of Gene Expression

Binding of toxicant dysregulates transcription, transduction, extracellular signal production (pathway)

Ex: Benzo[a]pyrene activates the transcription regulator protein, AhR, turning on gene expression (undesired)

Dysregulation of Ongoing Cellular Function

Includes dysregulation of electrically excitable cells (neurons, skeletal, cardiac)

Ex: Nicotine can inhibit nicotinic acetylcholine receptors → paralysis

List and describe how ATP levels can be affected by toxicants and result in impaired internal cell maintenance

1. Cocaine, CO, CNS depressants inhibit O2 delivery

2. Paraquat, doxorubicin, cyanide inhibits electron transport chain

3. DDT inhibits ADP phosphorylation

4. Arsenite, ethanol inhibits H2 delivery

ATP is vital, therefore anything that inhibits ATP production → toxic

Give examples of the general ways by which toxicants can cause target molecule dysfunction and destruction

Dysfunction: Enzyme & receptor inhibition, binding to transcription regulator proteins in the nucleus

Destruction: Lipid peroxidation (destroying lipid membranes), DNA radiation damage

Neoantigen Formation

Covalent binding of toxicant to cellular protein elicits an immune response (direct interaction)

Toxicity not initiated by reaction with target molecules

Some toxicants alter the biological environment instead of direct reaction with target → toxic response

Changing pH, changing solvents (alter lipid formation), sterics

Agonist

Binds to a receptor, mimicking its endogenous ligand → activates it

Antagonist

Blocks the endogenous ligand