Toxicology: Individual Differences & Dose-Response

Individual Differences in Toxic Response

• Significant inter-individual variations in chemical response exist within a species due to subtle genetic differences.
• Genetic polymorphisms (hereditary differences in a single gene affecting >1% of the population) contribute to these variations.

Dose-Response Relationships

• Dose: The amount of a chemical or physical agent contacting a living organism.
• Median Effective Concentration (MEC/ED50): The plasma concentration producing a therapeutic effect in 50% of the population; reflects the concentration at the receptor site for the desired response. Concentrations below the MEC are sub-therapeutic.
• Median Toxic Concentration (MTC/TD50): The plasma concentration triggering adverse effects in 50% of the population; also known as the maximum safe concentration (MSC). Concentrations above the MTC are toxic.
• Median Lethal Concentration (LC50): The concentration expected to kill 50% of a population under defined conditions.

Toxic Effects vs. Side Effects

• Side Effects: Undesirable but unavoidable effects occurring at normal dosages.
• Toxic Effects: Adverse effects usually seen at higher doses; often irreversible but treatable; may be related or unrelated to the main pharmacological action. Examples include bleeding with warfarin and liver toxicity from paracetamol.

Spectrum of Undesired Effects

• Allergic Reactions: Immunologically mediated reactions due to prior sensitization to a chemical or a similar one; the chemical often combines with an endogenous protein to form an antigen (hapten).
• Idiosyncratic Reactions: Abnormal reactivity to a chemical due to inherent factors; can involve extreme sensitivity to low doses or insensitivity to high doses.
• Immediate Toxicity: Rapidly occurring effects after single administration.
• Delayed Toxicity: Effects occurring after a time lapse; e.g., carcinogenic effects often have a long latency period (20-30 years).
• Reversible Effects: Tissue injury with regeneration capacity (e.g., liver); CNS injury is largely irreversible.
• Irreversible Effects: Carcinogenic and teratogenic effects are usually irreversible.
• Local Effects: Occur at the initial contact site; e.g., chlorine gas damaging lung tissue.
• Systemic Effects: Require absorption and distribution to a distant site for effects.

Chemical Interactions

• Chemical interactions can alter absorption, protein binding, biotransformation, and excretion of interacting agents.
• Types of interactions include additive, synergistic, potentiative, and antagonistic effects.

Selective Toxicity

• A chemical injures one kind of living matter without harming another (in intimate contact).
• The injured matter is "uneconomic," and the protected is "economic."
• Selectivity arises from differences in absorption, biotransformation, or excretion.

Species Differences in Toxic Response

• Significant response variations exist even among phylogenetically similar species (e.g., rats, mice).
• Understanding these differences is crucial in toxicology.

Therapeutic Index (TI)

• Compares the amount of a therapeutic agent causing a therapeutic effect to the amount causing toxicity. Also called the therapeutic window.

Drug Development Process

• Step 1: Discovery and development of a lead compound.
• Step 2: Preclinical research.
• Step 3: Clinical research.
• Step 4: FDA review.
• Step 5: FDA post-marketing safety monitoring.

Descriptive Animal Toxicity Tests

• Widely used for testing drug and other substance safety and efficacy, primarily using rats and mice.
• Standardized methodologies allow for comparison of results.
• Pharmacokinetic Studies: Provide information on absorption, distribution, metabolism, and elimination; crucial for interpreting results and extrapolating to humans.

Two Main Principles of Animal Toxicity Tests

• Effects in animals, when properly qualified, are applicable to humans.
• High-dose exposure in animals is necessary to discover potential human hazards.

Types of Animal Toxicity Tests

• Acute toxicity testing
• Skin and eye irritation testing
• Sensitization testing
• Sub-acute, sub-chronic, and chronic testing
• Developmental and reproductive toxicity testing
• Mutagenicity testing
• Oncogenicity bioassays
• Neurotoxicity assessment
• Immunotoxicity assessment

Genetic Toxicity

• Assesses deleterious effects of chemicals/agents on hereditary material and genetic processes.
• DNA damage can lead to mutations, genetic disorders, congenital defects, or cancer.

Toxicogenomics Tools

• Genomics: Characterization of all or part of an organism's genome.
• Transcriptomics: Characterization of all or most mRNAs expressed in a cell/tissue.
• Proteomics: Characterization of most or all proteins expressed in a cell/tissue.
• Metabonomics: Characterization of small molecules (substrates, products, co-factors) in a cell/tissue.