INTRODUCTION TO GENERAL TOXICOLOGY: TYPES OF EFFECTS

In toxicology, the type of effect produced by a poison depends on where and how the toxicant acts in the body. Toxic effects are broadly classified into ̶ 

• local 

• remote (systemic)

• combined effects.

Understanding types of poisoning effects is essential for

clinical recognition, management of poisoning, and risk assessment.

 LOCAL EFFECTS

• occur at the site of contact between the poison and the body.

• The effect is confined to the area of administration

• Could be oral or inhalation

LOCAL EFFECTS

• examples

• Corrosives (acids)

• Caustics (alkalis)

Corrosives (acids)

• example

• Sulfuric acid (H₂SO₄) on the cornea

Corrosives (acids)

Causes coagulative necrosis (protein denaturation → tissue solidification). The tissue hardens and dies

Caustics (alkalis)

• example

Sodium hydroxide (NaOH) on the cornea

Caustics (alkalis)

• Causes liquefactive necrosis (deep tissue penetration → perforation; enzymatic digestion). That enzymatic digestion leads to liquefaction which is brought about by pus formation caused by infection

• May lead to secondary bacterial or fungal infection

coagulative necrosis

(protein denaturation → tissue solidification

 liquefactive necrosis

deep tissue penetration → perforation; enzymatic digestion

 REMOTE  EFFECTS

• going to the blood which means, the poison is absorbed 

• the effect is produced in an area other than the site of application

• systemic effects require the absorption and distribution of a toxicant from its entry point to a distant site where the deleterious effects are produced

REMOTE  EFFECTS

• example

Atropine, when taken orally, is absorbed systemically and exerts anticholinergic effects that act on the eyes, leading to blurred vision

COMBINED

• The poison possesses both local and remote effects

• These substances cause direct tissue injury at the site of contact and toxic effects after systemic absorption

Local effect of Phosphorus

cutaneous burns

Systemic effect of Phosphorus

hepatic and renal failure

Local effect of Cantharidin

vesicant (blistering)

Systemic effect of Cantharidin

aphrodisiac and irritates the genitourinary system

Irritants/Corrosives – Effect

tissue necrosis on contact; caustic effect

Irritants/Corrosives- examples

Acids and alkalis

Neurotics/Neurotoxic – Effect

Affect CNS

Neurotics/Neurotoxic – Examples

Hallucinogens

Carcinogenic

• effect

Stimulate proliferation of cancer cells

Carcinogenic

• examples

• Nitrosamines

• aflatoxins

Asphyxiants

• effect

• Cause dyspnea

• Cause complete suspension of respiration

Asphyxiants

• examples

• CO

• methane gas

Lacrimators

• effect

Stimulate flow of tears from lacrimal glands

Lacrimators

• examples

• Cholinergics

• Carbamates

• Organophosphates

Sternutators

• effect

Stimulate excessive sneezing

Sternutators

• examples

• Strychnine

• Veratrine

Asthenics

• effect

• Produce muscularweakness

• “Exhaustives”

Asthenics

• examples

• Tubocurarine

• NM blockers

Narcotics

• effect

Produce mental weakness and depression, stupor, coma, respiratory depression

Narcotics

• examples

Opioids

CLASSIFICATION OF TOXIC AGENTS

• Use

• Source

• Target organ

• Effects

• Physical state

• Chemical stability

• General chemical structure

• Poisoning potential

• Label requirements

• Biochemical mechanism of action

Use

pesticide, solvent, food additive, etc.

Source

animal and plant toxin

Target organ

liver, kidney, hematopoietic system, etc.

Effects

cancer, mutation, liver injury, etc.

Physical state

gas, dust, liquid

Chemical stability

explosive, flammable, oxidizer

General chemical structure

aromatic amine, halogenated hydrocarbon, etc.

Poisoning potential

extremely toxic, very toxic, slightly toxic, etc.

Biochemical mechanism of action

e.g., alkylating agent, sulfhydryl inhibitor, methemoglobin producer

 WHAT ARE UNDESIRED EFFECTS?

The effects of chemicals—especially drugs—exist along a spectrum. Not all effects are intended, and not all unintended effects are harmful.

Therapeutic effect

the desired action

Side effects

• unintended effects that may or may not be harmful

• Prescription drugs often produce multiple effects, but usually:

  • Only one effect is intended

  • All others are considered side effects

Some side effects can be:

• Acceptable

• Beneficial in another context

Adverse (toxic) effects

• effects that are always harmful

• Never desirable unintended 

• Always detrimental to wellbeing

SIDE EFFECTS VS ADVERSE (TOXIC) EFFECTS

• clinical relevance

Risk–benefit analysis hinges on distinguishing tolerable side effects from unacceptable toxicity

• Adverse effects may be part of the drug’s identity or current characteristics and are managed by dose reduction, changing the medication, or discontinuation after risk–benefit assessment, especially when risk outweighs benefit

• Extra care, proper protocol, monitoring, and continuous lab tests are needed to determine tolerability of drugs with narrow therapeutic index or high potency

ALLERGIC (HYPERSENSITIVITY) REACTIONS

• A chemical allergy is an immune- mediated adverse reaction that occurs after prior exposure (sensitization).

  • IgE antibodies are activated after first exposure to an allergen. No reaction occurs the first time, but subsequent exposures can trigger a reaction. If hypersensitive to a drug, it is contraindicated

ALLERGIC (HYPERSENSITIVITY) REACTIONS

• Key Characteristics

• Requires previous exposure

• Can occur at very low doses

• Dose-related within a sensitized individual

• Often unpredictable

ALLERGIC (HYPERSENSITIVITY) REACTIONS

• Severe Outcomes

• Food allergies (nuts, shellfish)

• Antibiotic hypersensitivity

• Potentially fatal anaphylaxis

IDIOSYNCRATIC REACTIONS

•  refers to abnormal and unpredictable responses based on individual susceptibility.

  • Dose independent adverse reaction

Idiosyncratic toxicity arises from

individual susceptibility, often involving reactive metabolites, impaired detoxification, immune mechanisms, and programmed cell death

IDIOSYNCRATIC REACTIONS

contributing factors

• Formation of reactive intermediates

• Impaired detoxification

• Immune recognition (HLA-related)

• Cell death pathways abnormal

IDIOSYNCRATIC REACTIONS

examples

• Carbamazepine → Stevens–Johnson syndrome (SJS/TEN) (HLA-B*1502 association in Asians)

• Acetaminophen → Severe hepatotoxicity in susceptible individuals (not purely dose-related in idiosyncratic cases)

IDIOSYNCRATIC REACTIONS

additional modifiers

• Infection

• Inflammatory stress

• Mitochondrial dysfunction

• Environmental exposure

IDIOSYNCRATIC REACTIONS

Clinical Pattern

• Delayed onset after starting therapy

• Often affects:

  • Skin

  • Liver

  • Hematopoietic system

  • Immune system

Reversibility depends on the

• regenerative capacity of the affected tissue.

REVERSIBLE TOXICITY

• Liver (e.g., alcoholic stopped drinking, 3 months of liver aid)

• Gastrointestinal tract

IRREVERSIBLE TOXICITY

• Central nervous system (brain)

• Cancer 

• Birth defects

REVERSIBLE VS IRREVERSIBLE TOXIC EFFECTS

• clinical relevance

Prevention is crucial when damage cannot be repaired.

CHEMICAL INTERACTIONS

Humans are exposed to multiple chemicals simultaneously—from food, drugs, cosmetics, and the environment.

Types of interactions

• additive

• synergistic

• potentiation

• antagonism

Additive- ADD

• effects sum up (2 + 3 = 5)

ex 2 CNS depressants taken together at low doses

Synergistic- SUPER STRONG

• effect is amplified (2 + 2 = 20)

ex Alcohol + sedatives → profound CNS depressionSmoking + asbestos → markedly increased lung cancer risk

Potentiation- POWER BOOST

• non-toxic agent increases toxicity (0 + 2 = 10) 

enzyme inducers increasing toxicity of co-administered drugs

Antagonism- ANTI/ BLOCK

reduced effect – antidotes counteracting poisons

Antagonism in toxicology and pharmacology refers to a situation where .

one substance reduces or counteracts the effect of another

Antagonism is clinically important because

it forms the basis of antidote therapy and emergency management of poisoning.

Receptor antagonism

• compete at the same receptor

• Ex: BB antagonizing the beta agonist effect, competing at the same receptor

Chemical antagonism

• direct chemical inactivation 

e.g., chelators EDTA, BAL (sequestering agents) bind poisons and inactivate their toxicity

Dispositional antagonism

• alters ADME  pharmacokinetic  processes 

Ex: Activated charcoal, taken after poison ingestion; it decreases absorption of the poison

Functional antagonism

opposing physiological effects via different pathways

 Clinical Example of Functional Antagonism

Barbiturate-induced hypotension reversed by norepinephrine. Barbiturates decrease blood pressure; norepinephrine increases BP, antagonizing the effect.

TOLERANCE

• is a reduced response following repeated exposure

Cross-tolerance

• structurally related chemicals

• Ex: Morphine reduces the response to fentanyl

Dispositional tolerance

• decreased concentration at site of action

• Ex: Chronic alcohol use induces hepatic CYP enzyme

Cellular tolerance

• receptor downregulation or mediator depletion

• Ex: Repeated opioid exposure; workers exposed to NTG get headaches at first, by Friday, no headache due to cellular tolerance, but after weekend rest, headaches return Monday from vasodilation, extreme headaches on weekdays.